Twisted amide analogues of Troeger's base

Article abstract of DOI:10.1002/chem.201103228

Let's do the twist: The first twisted bis-amide (see figure) is obtained by the benzylic oxidation of Troeger's base (TB). Kinetic studies of its acidic hydrolysis reveal that the hydrolysis is to a large extent funneled through doubly protonated species. Copyright

Full text of DOI:10.1002/chem.201103228

DOI: 10.1002/chem.201103228
Twisted Amide Analogues of Trçgerꢀs Base
Josep Artacho,[a] Erhad Ascic,[a] Toni Rantanen,[b] Josefine Karlsson,[a]
Carl-Johan Wallentin,[a] Ruiyao Wang,[b] Ola F. Wendt,[a] Michael Harmata,*[c]
Victor Snieckus,*[b] and Kenneth Wꢁrnmark*[a]
In memory of Professors Manfred Hesse and Jan Sandstrçm
Trçgerꢀs base (TB),[1] 2,8-dimethyl-6H,12H-5,11-methano-
dibenzo-[b,f][1,5]-diazocine (rac-1), is a rigid chiral molecule
alkylation,[11] cleavage and replacement of the methylene
ACHTUNGTRENNUNG
G
bridge,[12] and direct exchange of the methylene for other
bridges by various methods.[13]
with a concave V-shaped aromatic surface (Figure 1). These
As part of our ongoing work,[6–10,14] we aimed to devise
new synthetic chemistry for the functionalization of the
chiral cleft of TB in order to provide new derivatives for
studies in catalysis and molecular recognition. In the course
of these studies, we serendipitously prepared the first TB
twisted bis-amide (rac-4). The availability of 4 logically
stimulated studies of its unusual structural, physical, and
chemical properties, including hydrolysis to form 7.
Figure 1. Trçgerꢀs base (TB) (rac-1) and 3D representation of the energy
Hence, in pursuit of C6 and C12 functionalization of TB,
we adapted and varied our previously developed condi-
tions,[14] using DMF as the electrophile quench. With
TMEDA/sBuLi (1 equiv), the aldehyde rac-2 was obtained
in poor yield (Scheme 1; see the Supporting Information).
minimized structure (Merck Molecular Force Field) of the S,S-isomer of
1.
intriguing properties have rendered TB and its analogues at-
tractive building blocks for exploitation and application in
molecular recognition, catalysis, enzyme inhibition and as
torsional balances.[2–4] Although TB itself and TB analogues
containing electron-rich substituents are prepared by a
simple procedure,,[1,5] access to other analogues has been
hampered by the absence of general methodologies to func-
tionalize the TB bicyclic diazocine core. Thus, although aryl
ring functionalization is well developed,[6–10] derivatization
of the diazocine ring has been limited to N-mono and –di-
Scheme 1. Formylation of TB (rac-1) and oxidation to mono-amide rac-3.
However, upon exposure of a CDCl3 solution of rac-2 to air,
a change in color was observed, leading to the isolation and
characterization (1H NMR and GC-MS) of rac-3, which was
most probably formed by the aerial oxidation of rac-2 to the
corresponding acid followed by oxidative decarboxylation.[15]
This finding[16] encouraged the study of the direct oxidation
of rac-1 in order to devise a method for the preparation of
the potentially fascinating twisted bis-amide analogue rac-4.
Following the screening of a variety of oxidizing agents
(Mn, Cr salts, Ru catalysts, hypervalent iodine), the opti-
mized conditions of KMnO4 (3 equiv) and benzyltriethylam-
monium chloride (BTEAC) in anhydrous CH2Cl2 at reflux
for 9 h were established and afforded lactam rac-3 in 25%
yield (see the Supporting Information) together with 30%
of unreacted starting material.[17] In a second lengthy optimi-
zation study, conditions of KMnO4/BTEAC (9 equiv) at
reflux in CH2Cl2 for 4 h led to the bis-lactam rac-4 in 28%
yield, as well as 15% and 5% of the quinazoline by-prod-
[a] J. Artacho, E. Ascic, J. Karlsson, Dr. C.-J. Wallentin,
Prof. O. F. Wendt, Prof. K. Wꢁrnmark
Centre for Analysis and Synthesis
Department of Chemistry, Lund University
P. O. Box 124, 22100 Lund (Sweden)
Fax : (+46)46-2228209
E-mail: kenneth.warnmark@organic.lu.se
[b] Dr. T. Rantanen, Dr. R. Wang, Prof. V. Snieckus
Department of Chemistry
Queenꢀs University
Kingston, ON, K7L 3N6 (Canada)
E-mail: snieckus@chem.queensu.ca
[c] Prof. M. Harmata
Department of Chemistry, University of Missouri-Columbia
Columbia, MO, 65211 (USA)
E-mail: harmatam@missouri.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103228.
1038
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Chem. Eur. J. 2012, 18, 1038 – 1042

COMMUNICATION
the X-ray structure, the twist angle,[24] describing the devia-
tion from co-planarity between the carbonyl p orbital and
the nitrogen lone pair, was determined to be t=ꢀ43.78 for
TB analogue rac-4 as compared to the near t=08 and t=
1808 commonly found in unconstrained cisoid and transoid
amides, respectively.[24] Furthermore, the overall distortion
parameter q,[25] an additive term that provides a quantitative
description of the combined deformation or pyramidality of
the nitrogen and carbonyl carbon together with the twist
angle, was determined to be q =106.18 (see the Supporting
Information), whereas that of a simple planar amide is q=
08.[25] Owing to the presence of two such amide functionali-
ties in the molecule, rac-4 is classified as twisted bis-amide,
and is, to our knowledge, the first example of such a com-
pound reported to date. Interestingly, twisted bis-amide rac-
Scheme 2. Synthesis of the twisted bis-amide rac-4 by direct oxidation of
TB rac-1.
ucts 5 and 6 (Scheme 2),[18,19] respectively, whose structures
1
are supported by H NMR and HRMS-ESI analysis.
ꢀ
It appears that the use of dichloromethane plays an im-
portant role in the reaction since attempts to perform the
oxidation reaction in benzene at different temperatures led
only to the recovery of the starting material. The structures
of rac-4 and 5 were unambiguously established by X-ray dif-
fraction analyses (see Figure 2 and the Supporting Informa-
4 has the shallowest cavity and the longest C2 C8 distance
of all TB analogues, including Hardingꢀs all-carbon analogue
of rac-4, a diketone of dibenzobicycloACTHNUTRGNEUNG[3.3.1]nonane (see the
Supporting Information for comparison).[26] A consequence
of the aforementioned deformation is the unusual bond
ꢀ
lengths. The crystal structure of rac-4 shows C(O) N and
C=O bond lengths of 1.437 and 1.209 ꢃ, substantially longer
and shorter than those of the unconstrained tertiary lactam,
1-methyl-2-piperidone [1.352 and 1.233 ꢃ, respectively (t=
2.58 and q=17.18)][27] and similar to the lengths of Kirbyꢀs
very twisted 1-aza-2-adamantanone [1.475 and 1.195 ꢃ, re-
spectively (t=90.58 and q=150.08)].[23b] (See the Supporting
Information for the calculation of q data.) Abnormal spec-
troscopic features for the carbonyl group are also common
in twisted amides. Twisted bis-amide rac-4 shows an IR ab-
sorption at n˜C 1694 cmꢀ1. This value is significantly higher
=
O
than that of unconstrained 1-methyl-2- piperidone (n˜C of
=
O
1653 cmꢀ1)[23c] but not as high as for the twisted 1-aza-2-ada-
Figure 2. ORTEP representation of the crystal structure of twisted bis-
amide rac-4. Hydrogen atoms, have been omitted for clarity.
mantanone (n˜C 1732 cmꢀ1),[23b,c] Interestingly, the IR C=O
=
O
absorption band of Hardingꢀs all-carbon analogue of rac-4,
is at lower frequency (n˜C of 1660 cmꢀ1) compared to rac-
=
O
tion). Rationalization of the formation of the interesting by-
4.[28] Based on the comparison of the IR spectra of rac-3 and
products 5 and 6 relates somewhat to the hydrolytic study in
rac-4, we suggest that mono- lactam rac-3, showing n˜C
=
O
that the N C(O) bond is cleaved (see below). The incorpo-
1698 cmꢀ1, is also a twisted amide. The 13C NMR chemical
shifts for the carbonyl carbon resonance are also susceptible
to variations, although to a much lesser extent.[29] Hence, the
shifts of the 13C resonance for rac-4 and 1-methyl-2-piperi-
done (d=170.1 ppm and d=165 ppm), do not differ mark-
edly, both being in the range of a regular amide.
ꢀ
ration of a methylene in 5 and 6 suggests that a probable
mechanism for their formation is first oxidation of the ben-
zylic methylenes to give rac-4 followed by a net oxidative
ꢀ
cleavage of the resulting N C(O) bond that, owing to its
ꢀ
twisted nature, is weaker than a normal N C(O) bond. The
carboxylate then undergoes reaction once or twice with di-
chloromethane in the presence of the phase transfer catalyst
to form the corresponding monomeric or dimeric esters, re-
spectively.[20] During these processes, the compound under-
goes oxidation to the final dihydroquinazolines 5 and 6. Di-
hydroquinazolines are well-known by-products in the syn-
thesis of TB.[21]
To probe the reactivity of the amide functionality of rac-4,
kinetic analyses of its acid-catalyzed hydrolysis was under-
1
taken. The hydrolysis was investigated by H NMR spectros-
copy in a mixture of CD3CN/D2O (8:2). Pseudo-first-order
kinetics were observed at different concentrations of DCl
(0.058 to 0.87m) at room temperature. The structurally simi-
lar reference compounds, N,N-dimethylbenzamide and N-
methylpiperidone, did not undergo hydrolysis in a 0.58m so-
lution of hydrochloride acid, whereas twisted amide rac-4
was converted to hydrolysis product 7 (Scheme 3) with com-
plete disappearance of rac-4 within 400 min (see the Sup-
porting Information). This difference in reactivity is attribut-
X-ray solid-state structure analysis revealed that rac-4 is
an example of the relatively rare class of twisted amides
(Figure 2).[22] In such amides, steric repulsion or structural
constraints impede the overlap of the nitrogen lone-pair
electrons with the carbonyl p bond,[23] giving the amide func-
tionality unusual physical and chemical properties. Based on
ꢀ
ed to the weaker N C(O) bond in rac-4. In fact, DFT calcu-
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1039

K. Wꢁrnmark, M. Harmata, V. Snieckus et al.
mental
data
convincingly
shows that the denominator is
insignificantly different from
unity (Figure 3). Thus, Equa-
tion (1) simplifies to Equa-
tion (2)
and,
from
the
fitted values, k1K1 =6.9ꢁ3.0
10ꢀ3 mꢀ1 sꢀ1 and k2K1 K2 =3.2ꢁ
0.4 10ꢀ2 mꢀ2 sꢀ1 were obtained.
This implies that at [H+]>
0.21m, a majority of the prod-
uct is funneled through the
doubly protonated intermedi-
ate rac-9. The fact that the de-
nominator is very close to
Scheme 3. One kinetic model involving single and double reversible protonation of twisted bis-amide rac-4 fol-
lowed by reversible formation of two tetrahedral intermediates rac-8 and rac-9, before irreversible formation
of product 7, in agreement with the experimental data.[32] The structure of rac-8 and rac-9 are suggested and
are based on the sites of protonation of rac-4 obtained from the DFT calculations and 18O labeling studies.
lations B3LYP/6-311G**) (see the Supporting Information)
show that the preferred site of protonation is on the nitro-
gen of rac-4, by 3.5 kcalmolꢀ1 compared to oxygen,[30,31]
unity also implies that the equilibria defined by K1 and K2
are very strongly shifted towards the left at the investigated
concentrations of acid. It has been proposed that hydrolyses
of distorted amides occur through the sequential formation
of first protonated and then tetrahedral intermediates by
equilibrium reactions followed by an irreversible step.[23a]
From our data alone it is not possible to distinguish whether
waters enters in the reversible or in the irreversible step. To
probe for the involvement of reversibly formed tetrahedral
intermediates, we performed the hydrolysis of rac-4 using
90% 18O labeled water at 228C and [H+]=0.174m.
ꢀ
making the N C(O) bond exceptionally long, 1.61 ꢃ, much
longer compared to calculated bond lengths of other N-pro-
tonated bicyclic lactams.[23f] This facilitates the breaking of
ꢀ
the N C(O) bond in the subsequent nucleophilic addition
of water. Interestingly, the DFT calculations show that the
LUMO of N-protonated rac-4 has almost no contributions
from orbitals on nitrogen, but has large lobes on the carbon-
yl group and the adjacent aromatic carbon, indicating the
acylium ion character of N-protonated rac-4. This depiction
is further supported by the change in bond angles from
2
k1K1½Hþꢂ þ k2K1K2½Hþꢂ
ð1Þ
ð2Þ
kobs
¼
2
1 þ K1½Hþꢂ þ K2½Hþꢂ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
123.58 to 132.58 (C6’ C6 O) and 13.78 to 1.58 (C7 C6’ C6
O) for 4 and N-protonated rac-4, respectively. The latter in-
kobs ¼ k1K1½Hþꢂ þ k2K1K2½Hþꢂ
2
ꢀ
dicating that the C6 N5 bond is almost broken and that the
incipient acylium ion is becoming conjugated with the aro-
matic moiety of N-protonated rac-4. The hydrolysis rate of
rac-4 should be compared to Kirbyꢀs twisted amide (see
above) for which hydrolysis takes approximately 1 min at
very low concentrations of acid,[23b] reflecting its higher twist
angle and consequently higher reactivity relative to the
amide rac-4. The product of the hydrolysis, amide 7, was
A mass analysis of the reaction mixture at approximately
50% conversion (see the Supporting Information) revealed
that the distribution of non-18O labeled product 7, singly 18O
labeled 7, doubly 18O labeled 7, and triply 18O labeled 7 was
approximately 21:100:53:11.[31] The distribution of non-18O
labeled to singly 18O labeled starting material rac-4 was ap-
proximately 100:7. The 18O-incorporation in rac-4 indicates
1
characterized directly in the reaction mixture by H NMR,
2D NMR, and ESI-MS (see the Supporting Information).
As expected, the normal amide 7 does not undergo hydroly-
sis under the conditions of the reaction. The observed rate
constants, kobs were obtained by fitting a single exponential
model to the observed decay of starting material at a given
concentration of acid, that is, the reaction is first order with
respect to rac-4 as the limiting reagent. The quality of the
fits was excellent as measured by the regression coefficient,
R (see the Supporting Information). The kobs values show a
clear dependence on proton concentration and, as seen from
Figure 3, the dependence is clearly higher order in [H+]. To
explain this behavior, we propose a mechanism involving
single and double protonation and nucleophilic attack by
water giving intermediates rac-8 and rac-9, both of which
are irreversibly converted to product 7 (Scheme 3). Deriving
the rate law from this mechanism gives the expression in
Equation (1). Other models were also investigated (see the
Supporting Information). Fitting Equation (1) to the experi-
Figure 3. Observed rate constants for the hydrolysis of rac-4 at different
concentrations of acid denoted by “o”. The fitting of the two kinetic
models ([Eq. (1)]; R=0.99751) and ([Eq. (2)]; R=0.99754) to the data
denoted by one solid line (both models coincide).
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Twisted Amide Analogues of Trçgerꢀs Base
COMMUNICATION
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intermediates, rac-8 and rac-9, that is, water enters in the
equilibrium step according to Scheme 3.[33]
In summary, oxidation of the benzylic methylene(s) of TB
to carbonyl group(s) has been demonstrated for the first
time. The reaction conditions were tuned to produce either
the mono- (rac-3) or the bis- (rac-4) amide TB analogue. X-
ray diffraction analysis revealed rac-4 to be an example of
the relatively rare class of twisted amides and, to the best of
our knowledge, the first example of a twisted bis-amide. In
addition, compound rac-4 has the shallowest cavity of all TB
analogues investigated by X-ray diffraction analysis to date.
The acidic hydrolysis of rac-4 and “normal” amides was
studied and only rac-4 underwent hydrolysis under the con-
centration of acid employed, yielding amide 7. Kinetic inves-
tigations showed that 7 were formed from singly and doubly
protonated intermediates. Labeling studies showed that the
decomposition to 7 likely takes place irreversibly from
singly and doubly protonated tetrahedral intermediates. The
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reminiscent of that of b-lactam antibiotics and merits struc-
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Acknowledgements
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K.W thanks the Swedish Research Council, the Royal Physiographic So-
ciety in Lund, the Crafoord Foundation, and the Swedish Foundation for
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Sundin is thanked for DFT calculations.
Keywords: hydrolysis · oxidation · Trçgerꢀs base · twisted
amides · X-ray structures
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K. Wꢁrnmark, M. Harmata, V. Snieckus et al.
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bicycloACTHUNRTGNEUNG[3.3.1]nonan-2-one system, N-protonation seems slightly pre-
ferred over O-protonation (see references [23f,g,i]). However, those
calculations were carried out on a lower computational level than
ours.
[31] Isodesmic calulations of resonance energies (compare reference
[23g]) also support N-protonation (see the Supporting Information).
[32] The experimental data cannot distinguish whether rac-8 or rac-4·H+
is protonated giving compound 7.
[33] The 18O incorporation in 7 can be explained by 18O labeled water
exchanging with carboxyl group of 7 and attack of 18O labeled water
on protonated rac-4. The amide of 7 is a normal one and thus not
reactive. For 18O labeling studies on amides and carboxylic acids, see
a) R. S. Brown, A. J. Bennet, H. Slebocka-Tilk, Acc. Chem. Res.
1992, 25, 481–488; b) R. L. Redington, J. Phys. Chem. 1976, 80,
229–235, and references therein.
Received: October 12, 2011
1042
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