Huenlich base: (Re)discovery, synthesis, and structure elucidation after a century

Article abstract of DOI:10.1021/ol400357t

After almost 100 years, the structure of the product of the reaction between 2,4-diaminotoluene and formaldehyde was elucidated: derivative 3, which we call the Huenlich base, was synthesized on a multigram scale and its enantiomers were easily separated in preparative amounts. Furthermore, transformation of the NH₂ groups to the corresponding bis-iodides and bis-azides is presented. The latter was also used for desymmetrization by click chemistry.

Full text of DOI:10.1021/ol400357t

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1418–1420
€
Hunlich Base: (Re)Discovery, Synthesis,
and Structure Elucidation after a Century
Stephan Rigol,† Lothar Beyer,‡ Lothar Hennig,† Joachim Sieler,‡ and
Athanassios Giannis*,†
€
€
Institut fu€r Organische Chemie and Institut fu€r Anorganische Chemie, Fakultat fur
€
Chemie und Mineralogie, Universitat Leipzig, Johannisallee 29, 04103 Leipzig, Germany
giannis@uni-leipzig.de
Received February 7, 2013
ABSTRACT
After almost 100 years, the structure of the product of the reaction between 2,4-diaminotoluene and formaldehyde was elucidated: derivative 3,
€
which we call the Hunlich base, was synthesized on a multigram scale and its enantiomers were easily separated in preparative amounts.
Furthermore, transformation of the NH2 groups to the corresponding bis-iodides and bis-azides is presented. The latter was also used for
desymmetrization by click chemistry.
Serendipity, the “faculty of making happy and unex-
pected discoveries” plays an important role in science and
technology, and in the past, countless of accidental dis-
coveries have been reported.1aꢀc In this paper, we present
such an example which occurred during the planning and
elucidation by Spielman in 1935,4 Prelog recognized the
€
chiral nature of Troger’s base (2,8-dimethyl-6H,12H-5,11-
methanodibenzo[b,f][1,5]diazocine) and was able to sepa-
rate chromatographically its enantiomers using lactose as
€
5
chiral stationary phase. The structure of Troger’s base
organization of the Symposium on the occasion of Julius
2
was confirmed by X-ray in 1986.6 In the past 125 years,
€
Troger’s 150th birthday last year in Leipzig, Germany.
€
a plethora of Troger’s base analogues have been syn-
thesized7aꢀc and used in the development of synthetic
(4) Spielman, M. A. J. Am. Chem. Soc. 1935, 57, 583–585.
(5) Prelog, V.; Wieland, M. Helv. Chim. Acta 1944, 27, 1127–1134.
(6) Larson, S. B.; Wilcox, C. S. Acta Crystallogr. Sect. C 1986, 42,
224–227.
(7) Leading reviews: (a) Sergeyev, S. Helv. Chim. Acta 2009, 92, 415–
ꢀ
ꢀ
´
444. (b) Dolensky, B.; Elguero, J.; Kral, V.; Pardo, C.; Valık, M. Adv.
€
ꢀ
Heterocycl. Chem. 2007, 93, 1–56. (c) Runarsson, O. V.; Artacho, J.;
Warnmark, K. Eur. J. Org. Chem. 2012, 7015–7041. Synthetic receptors:
€
(d) Adrian, J. C.; Wilcox, C. S. J. Am. Chem. Soc. 1989, 111, 8055–8057.
(e) Wilcox, C. S.; Adrian, J. C.; Webb, T. H.; Zawacki, F. J. J. Am. Chem.
Soc. 1992, 114, 10189–10197Molecular torsion balances:. (f) Paliwal, S.;
Geib, S.; Wilcox, C. S. J. Am. Chem. Soc. 1994, 116, 4497–4498. (g) Kim,
E.-I.; Paliwal, S.; Wilcox, C. S. J. Am. Chem. Soc. 1998, 120, 11192–
11193. (h) Hof, F.; Scofield, D. M.; Schweizer, W. B.; Diederich, F.
Angew. Chem. 2004, 116, 5166–5169. Angew. Chem., Int. Ed. 2004, 43,
5056–5059. (i) Bhayana, B.; Wilcox, C. S. Angew. Chem., Int. Ed. 2007,
46, 6833–6836. (j) Fischer, F. R.; Schweizer, W. B.; Diederich, F. Angew.
Chem. 2007, 119, 8418–8421. Angew. Chem., Int. Ed. 2007, 46, 8270–
€
Figure 1. Troger’s base.
€
In 1887, Julius Troger reported on the synthesis of base 1
(Figure1) identifiedwithhisname.3 Followingitsstructure
† Institut f€ur Organische Chemie.
‡ Institut f€ur Anorganische Chemie.
€
8273. Fullerenes: (k) Sergeyev, S.; Schar, M.; Seiler, P.; Lukoyanova, O.;
(1) (a) Roberts, R. M. Serendipity: Accidental Discoveries in Science;
John Wiley & Sons: Hoboken, 1989. (b) Ban, T. A. Dialogues Clin.
Neurosci. 2006, 8, 335–344. (c) Sneader, W. Drug Discovery: A History;
John Wiley & Sons: West Sussex, 2005.
Echegoyen, L.; Diederich, F. Chem.;Eur. J. 2005, 11, 2284–2294. (l)
Segeyev, S.; Diederich, F. Angew. Chem. 2004, 116, 1770–1773. Angew.
Chem., Int. Ed. 2004, 43, 1738–1740. Peptidomimetics: (m) Bew, S. P.;
Legentil, L.; Scholier, V.; Sharma, S. V. Chem. Commun. 2007, 389–391.
Asymmetric transformations: (n) Goldberg, Y.; Alper, H. Tetrahedron
Lett. 1995, 36, 369–372. (o) Minder, B.; Schiirch, M.; Mallat, T.; Baiker,
A. Catal. Lett. 1995, 31, 143–151.
(2) http://www.uni-leipzig.de/∼organik/Troeger/index.html, accessed
March 7, 2013.
€
(3) Troger, J. J. Prakt. Chem. 1887, 36, 225–245.
r
10.1021/ol400357t
Published on Web 03/07/2013
2013 American Chemical Society

receptors,7d,e investigation of intramolecular interactions,
design of molecular torsion balances,7fꢀh,i,j template
synthesis of fullerene derivatives,7k,l conformationally
restricted scaffolds for peptidomimetics,7m asymmetric
transformations,7n,o etc.
€
Hunlich’s base synthesis, whereas the methyl group pre-
vents (probably by steric hindrance) further reaction of the
formed product 3 with formaldehyde. Interestingly forma-
tion of the two other possible isomers 4 and 5 was not
observed.
Of particular interest for the above-mentioned investi-
€
Next we envisaged the isolation of both enantiomers
€
of Hunlich’s base. Toward this goal we first synthesized
amides 7 and 8 using N-Boc-L-phenylalanine and N-Boc-L-
gations are Troger’s base analogues carrying several sub-
stituents in the aromatic moiety of 1. Such functionalized
derivatives can be obtained usually by multistep procedures8
or following the original procedure or modifications of it.7
In the latter, anilines were condensed with formaldehyde or
its synthetic equivalent under acidic conditions. The amino
valine, respectively (Scheme 2).
€
derivatives of Troger’s base were not accessible by this route
since the reaction of diaminobenzenes with formaldehyde
obviously afforded polymeric products.9
Taking this into consideration, we were surprised to find
€
an old reaction described in 1914 by Walter Hunlich in his
Ph.D. thesis at the University of Leipzig (cover page of
€
thesis and the structures proposed by Hunlich in the thesis
are included in the Supporting Information).10 He con-
densed 2,4-diaminotoluene 2 with formaldehyde in the
presence of sulfuric acid and obtained gram amounts
(11ꢀ13% yield) of a crystalline solid with the molecular
formula C17H20N4.
€
Scheme 1. Synthesis of Hunlich’s Base
However, he was not able to determine the structure,
which remained obscure ever since (see the Supporting
€
Information). Hunlich died in World War I,and his work
was never published and subsequently forgotten. Driven
by curiosity and necessity, we decided to reinvestigate
€
Hunlich’s procedure and to elucidate the structure of the
formed product. We were pleased to isolate a crystalline
€
Figure 2. Drawings of Hunlich’s base 3 with thermal ellipsoids
scaled to 50% probability (top); detail of the elementary unit
showing CHꢀalkaneꢀaromatic interactions (bottom).
solid in 31ꢀ34% yield. The structure of this solid, which
€
we call “Hunlich’s base” (3, Scheme 1), was elucidated
by NMR spectroscopy and unambiguously confirmed by
X-ray diffraction analysis (Figure 2). Apparently and
contrary to the commonly accepted opinion, it is possible
to use at least 2,4-diaminotoluene in the frame of synthesis
€
of Troger’s base analogues. It appears that the amino
group in the para-position to the methyl group in 2,4-
The resultant diastereomers 7a and 7a0 as well as 8a and
8a0 were easily separated by chromatography and sub-
jected to alkaline hydrolysis to afford the pure enantiomers
3a and 3a0 in almost quantitative yield (Scheme 3).
Taking Wilen’s work11 into consideration, we assigned
structure 3a to the dextrorotatory enantiomer ([R]2D2 = þ58
diaminotoluene is more reactive under the conditions of
(8) Webb, T. H.; Wilcox, C. S. J. Org. Chem. 1990, 55, 363–365.
(9) Didier, D.; Sergeyev, S. Tetrahedron 2007, 63, 3864–3869.
€
(10) Hunlich, W. Uber ein neues Kondensationsprodukt von m-To-
€
(11) Wilen, S. H.; Qi, J. Z.; Williard, P. G. J. Org. Chem. 1991, 56,
485–488.
€
luylendiamin mit Formaldehyd. Ph.D. Thesis, Universitat Leipzig, 1914.
Org. Lett., Vol. 15, No. 6, 2013
1419

Scheme 2. Synthesis of Amino Acid Derivatives 7 and 8
Scheme 4. Synthesis of Bis-azido and Bis-iodo Derivatives
(c = 1, MeOH)) and formula 3a0 to the levorotatory one
([R]2D2 = ꢀ63 (c = 0.33, MeOH)). However, it should be
pointed out that this assignment is tentative as the absolute
configuration is still unclear.
€
In agreement with other studies using Troger’s base
derivatives, we observed racemization of 3a and 3a0 under
acidic conditions (t1/2 ≈ 12 h, 1.5 M HCl/EtOH).
Scheme 5. Desymmetrization by Click Chemistry
€
Scheme 3. Resolution of Hunlich’s Base Enantiomers
In summary, after almost 100 years, the structure of the
product of the reaction between 2,4-diaminotoluene and
formaldehyde was elucidated. In fact, derivative 3, which
€
we call Hunlich’s base, was synthesized on a multigram
scale, and its enantiomers were easily separated in pre-
parative amounts.
€
In addition, Hunlich’s base was transformed in one step
into the corresponding bis-iodo as well as into bis-azido
derivatives, which in turn are valuable starting materials in
the frame of transition-metal-catalyzed cross-coupling
reactions and click chemistry, respectively.9,15aꢀ15d
The presence of two free amino groups in compound 3
offers many possibilities for the facile entry to several
€
Hunlich’s base derivatives carrying additional functional
side chains. For example, transformation of Hunlich’s
€
€
The accessibility of Hunlich’s base and its derivatives
base into the corresponding bis-azide 9 as well as into the
bis-iodide 10 was possible in multigram-scale (Scheme 4).
It is important to note that bishalogeno derivatives of
in preparative amounts opens new possibilities in the fields
of chiral catalysis and chromatography, supramolecular
chemistry, and molecular recognition to name a few.
€
Troger’s base are accessibleunder the conditions published
by Warnmark, whereas bis-azides like 9 are usually
12
€
Acknowledgment. We thank Karin Richter and Renate
synthesized starting from the corresponding bromo- or
iodo-derivatives.13 Bis-azide 9 was also obtained via a
copper(I)-catalyzed diazo transfer under mild condi-
tions.14 In addition we were able to desymmetrize bis-azide
9 and to obtain triazoles 11 and 12 in the presence of
copper(I) salts starting from phenylacetylene and 1-octyne,
respectively, as depicted in Scheme 5.
€
Herold, both of the Institut fur Organische Chemie,
Fakultat fur Chemie und Mineralogie, Universitat Leipzig,
€
€
€
for support during the synthetic work.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org. CCDC 919389 con-
tains the supplementary crystallographic data for this
paper. This data can be obtained free of charge from
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK. Fax: (int)þ44-1223/
336-033. E-mail: deposit@ccdc.cam.ac.uk.
€
(12) Jensen, J.; Warnmark, K. Synthesis 2001, 1873–1877.
€
(13) Hansson, A.; Wixe, T.; Bergquist, K.; Warnmark, K. Org. Lett.
2005, 7, 2019–2022.
(14) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–3800.
€
(15) Suzuki and Sonogashira reactions: (a) Kiehne, U.; Lutzen, A.
€
Synthesis 2004, 1687–1695. (b) Hof, F.; Schar, M.; Scofield, D. M.;
Fischer, F.; Diederich, F.; Sergeyev, S. Helv. Chim. Acta 2005, 88, 2333–
2344. (c) Solano, C.; Svensson, D.; Olomi, Z.; Jensen, J.; Wendt, O. F.;
€
Warnmark, K. Eur. J. Org. Chem. 2005, 3510–3517. Buchwald reaction;
see ref 9 and: (d) Artacho, J.; Warnmark, K. Synthesis 2009, 3120–3126.
€
The authors declare no competing financial interest.
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Org. Lett., Vol. 15, No. 6, 2013