Novel 2,4-methanoadamantane-benzazepine by domino photochemistry of N-(1-adamantyl)phthalimide

Article abstract of DOI:10.1021/ol801362x

(Chemical Equation Presented) The photochemical reaction of N-(1-adamantyl)phthalimide (1) gives cleanly one product, the novel hexacyclic benzazepine derivative of 2,4-methanoadamantane 2. Its structure was characterized by spectroscopic methods and X-ray analysis and represent the first example of the 2-azahexacyclo[8.7.1.1^1,4.0^4,9.0 ^11,16.0^12,18]nonadeca-4,6,8-triene skeleton. The product is formed by a domino process of two consecutive excited-state intramolecular γ-hydrogen-transfer reactions. Base hydrolysis of the benzazepine 2 gives in high yield the keto derivative of the 1,2-substituted adamantane ε-amino acid 3.

Full text of DOI:10.1021/ol801362x

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3965-3968
Novel 2,4-Methanoadamantane-
Benzazepine by Domino Photochemistry
of N-(1-adamantyl)phthalimide
Nikola Basaric´,*,† Margareta Horvat,† Kata Mlinaric´-Majerski,†
Elmar Zimmermann,‡ Jo¨rg Neudo¨rfl,‡ and Axel G. Griesbeck*,‡
Department of Organic Chemistry and Biochemistry, Ru{er BosˇkoVic´ Institute,
10 000 Zagreb, Croatia, and Department of Chemistry, UniVersity of Cologne,
50939 Ko¨ln, Germany
nbasaric@irb.hr
Received June 17, 2008
ABSTRACT
The photochemical reaction of N-(1-adamantyl)phthalimide (1) gives cleanly one product, the novel hexacyclic benzazepine derivative of 2,4-
methanoadamantane 2. Its structure was characterized by spectroscopic methods and X-ray analysis and represent the first example of the
2-azahexacyclo[8.7.1.11,4.04,9.011,16.012,18]nonadeca-4,6,8-triene skeleton. The product is formed by a domino process of two consecutive excited-
state intramolecular γ-hydrogen-transfer reactions. Base hydrolysis of the benzazepine 2 gives in high yield the keto derivative of the 1,2-
substituted adamantane ε-amino acid 3.
The benzazepine skeleton is found in numerous biologically
active compounds.1 Synthetic methods for its preparation
include the formation of the C-N bond by nucleophilic
displacement of halogen by amines,2 cyclization of the
ε-amino hexanoic acid and its derivatives,3 or Beckmann
rearrangement of cyclohexanone oximes.4 The other synthetic
strategies to benzazepine derivatives are conducted via
isomerization of azides,5 ring expansion of arenes by
electron-deficient nitrenes,6 [2 + 2]-cycloaddition to aza five-
membered heterocycles followed by ring enlargement,7 ring
expansion of quinolines,8 or the formation of a C-C bond
in a Bischler-Napieralski cyclization of N-acyl-γ-phenyl-
propylamines.9
In the context of the research in the Majerski group on
the synthesis and chemistry of adamantane10 and strained
adamantane derivatives,11 we became interested in adaman-
tane phthalimides and the possibility of their photochemical
transformation to biologically active compounds such as
benzazepindiones. One of the pathways toward benzazepines
is the photochemical homolytic H-activation12 or electron
transfer initiated decarboxylative cyclization of phthalim-
* To whom correspondence should be addressed. (N.B.) Fax: +385 1
4680 195. (A.G.G.) Fax: +221 470 5057.
† Ru{er Bosˇkovic´ Institute.
‡ Cologne University.
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10.1021/ol801362x CCC: $40.75
Published on Web 08/21/2008
2008 American Chemical Society

Scheme 1. Mechanism of the Photochemical Transformation of N-(1-Adamantyl)phthalimide (1)
ides,13 which has been the subject of intensive research
interest.14 In this letter we report a highly selective photo-
chemical CH activation of N-(1-adamantyl)phthalimide (1)
giving a novel hexacyclic benzazepine and its hydrolysis to
a derivative of the 1,2-substituted adamantane ε-amino acid.
Preparation of cage amino acids is of high interest since it
is known that several peptidomimetics with cage amino acids
show anticancer activities.15
acetone/H2O (3:1). In all investigated solvents only one
product was formed. For example, 24 h photolysis in acetone
gave 2 in 82% yield. The pure product crystallized from the
solution upon evaporation of the solvent after photolysis and
no further purification was required. To our surprise, the
isolated product was not the anticipated benzazepindione
(B, Scheme 1), but a novel 2-aza-10-hydroxyhexacyclo-
[8.7.1.11,4.04,9.011,16.012,18]nonadeca-4,6,8-triene-3-one (2), hith-
erto not reported. In addition, 2 is a derivative of 2,4-
methanoadamantane (MAd), a strained compound involving
a cyclobutane ring and a boat cyclohexane ring in a rigid
tetracyclic system. There are only a few reports on the
synthesis of this cage system. MAd can be prepared in two
steps from ethanoadamantan-3-one18 involving diazotiza-
tion19 and photolysis.20 The other pathway to MAd involves
formation of a [3.1.1]propellane21 and its subsequent reduc-
tion with Li or by free radical reaction.22
The adamantane phthalimide 116 was synthesized from
1-aminoadamantane and phthalic anhydride using the pro-
cedure of Kidd and Sheehan.17 Photolysis of 1 was performed
in a Rayonet reactor at λ ) 300 nm under N2 in different
solvents: CH3CN, CH3CN/H2O (3:1), and acetone and
ˇ
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V.; Kojic´-Prodic´, B. Eur. J. Org. Chem. 1998, 1231. (c) Mlinaric´-Majerski,
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2923. (d) Safar-Cvitasˇ, D.; Savin, B.; Mlinaric´-Majerski, K. Croat. Chem.
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Tetrahedron 2007, 63, 7985. (h) Mlinaric´-Majerski, K.; Kragol, G.;
The MAd derivative 2 was characterized by spectroscopic
methods. In the IR spectrum of 2, the characteristic bands
corresponding to the amide NH and the alcohol OH vibra-
tions were observed at 3336 and 3238 cm-1, as well as the
amide CdO valence at 1634 cm-1. In the 1H NMR spectrum
of 2 (in CDCl3) in the aliphatic region two singlets showed
up at δ 6.16 and 2.04 ppm that were assigned to the protons
of NH and OH groups, respectively, which disappeared on
addition of D2O. In the 13C NMR spectrum (in DMSO-d6)
in the aliphatic region, four triplets, five doublets, and one
singlet were observed which correspond to the hexacyclic
structure. Furthermore, 2D homonuclear COSY and hetero-
nuclear HSQC spectra were also in accordance with the
assigned structure. The structure of product 2 was addition-
ˇ
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Eds.; CRC Press: Boca Raton, 2004; 1.
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82, 2020.
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3966
Org. Lett., Vol. 10, No. 18, 2008

ally proven by X-ray structural analysis (Figure 1).23 To the
best of our knowledge, this is the first example of the
1,4-biradical (BR-1, Scheme 1) is feasible.27 However, the
influence of the solvent polarity and proticity on the quantum
yield of the reaction suggest that BR-1 can also be formed
via intramolecular photoinduced electron transfer giving the
adamantane radical-cation28 and the phthalimide radical-
anion (BRI-1), followed by the intramolecular proton trans-
fer, a process that should be preferred in polar protic solvents.
When we performed photolysis of 1 (16 h, 100 mg in 200
mL of CH3CN/H2O 3:1) at pH 2 and 7, only product 2 was
obtained in 20% yield. On the other hand, at pH 10, the
conversion of 1 was lower (9%) and in addition to 2 smaller
amounts of side products were formed, but no attempt was
made to characterize them. These results suggest that
photoinduced intramolecular H-abstraction and intramolecu-
lar electron transfer (followed by the proton transfer) might
be competing processes but yet no unambiguous conclusion
can be made since under highly acidic and basic conditions
since ring opening of the phthalimide moiety takes place.
After cyclization, BR-1 gives azetidinol A which is
unstable and rapidly undergoes ring enlargement to azepin-
dione B.29 Subsequently, azepindione B undergoes a second
photochemical reaction which is more efficient than the first
transformation of 1. Namely, in the most stable conformer
of the azepindione, the distance between the H-atom at the
position 4 of the adamantane skeleton and the carbonyl
oxygen is only 2.3 Å.30 Therefore, efficient intramolecular
H-abstraction is anticipated giving biradical BR-2. The
cyclization of BR-2 furnishes the final product 2.
Figure 1.
ORTEP drawing of 2.23
2-azahexacyclo[8.7.1.11,4.04,9.011,16.012,18]nonadeca-4,6,8-
triene skeleton.
Photochemical transformation of 1 into 2 does not take
place in nonpolar solvents such as cyclohexane and occurs
very inefficiently in CH3CN (Φ ∼ 10-4).24 The reaction is
10 times more efficient in acetone, suggesting that it occurs
via the triplet excited state. Interestingly, the addition of a
protic solvent (H2O) to CH3CN or acetone increases the
quantum yield of the product formation by a factor of 2-3.
Low quantum yields of the reaction may be due to a ππ*
nature of the lowest excited-state of the phthalimide moiety
which is not reactive in the H-abstraction reactions.25
To obtain the ε-amino acid derivative, MAd benzazepine
2 was submitted to base hydrolysis. The hydrolysis performed
in refluxing 10% NaOH H2O/EtOH furnished 3 in high yield
(>80%). The structure of 3 was characterized by spectro-
1
scopic methods. Comparison of H NMR spectra (DMSO-
d6) of 2 and 3 indicated the disappearance of the signals
corresponding to the amide-NH and OH. Moreover, the
pattern of the aliphatic region of the spectrum after hydrolysis
was significantly simplified. The most important structural
information was obtained from the 13C NMR spectrum. Two
characteristic singlets were observed in the low field region
that were assigned to ketone CdO and carboxylic acid CdO
According to the product 2, we propose the reaction
mechanism as shown in Scheme 1. The triplet excited state
1 is formed either by acetone sensitization (vide supra) or
by direct excitation and ISC. In the most stable ground-state
conformer, the distance between the closest H-atom at the
adamantane skeleton (γ-H atom, position 2 of the adaman-
tane) and the phthalimide carbonyl moiety is only 2.4 Å.26
Thus, an intramolecular γ-H-transfer and formation of the
(27) (a) Ihmels, H.; Scheffer, J. R. Tetrahedron 1999, 55, 885. (b)
Leibovitch, M.; Olovsson, G.; Scheffer, J. R.; Trotter, J. J. Am. Chem. Soc.
1998, 120, 12755.
(28) The adamantane radical cation has been produced under photo-
chemical electron transfer conditions: Mella, M.; Freccero, M.; Albini, A.
Tetrahedron 1996, 52, 5533.
(29) We could not detect the presence of azepindione B even at low
conversion (<5%) photolysis of 1 by 1H NMR. In the UV spectra, an
increase in the bathochromic reagion appeared at low conversion and clear
non-isosbestic behavior was observed indicating an intermediate light-
absorbing species.
(23) X-ray data of compound 2: C18H19NO2 (281.34), T ) 100 K,
monoclinic, P21/c, a ) 11.8433(7) Å, b ) 8.0475(6) Å, c ) 14.4207(7) Å,
R ) γ ) 90°, ꢀ ) 96.435(3)°, V ) 1365.75(15) Å3, crystal size: 0.3 × 0.3
× 0.15 mm, θ range: 1.73-27.0°, reflections, collected 6486, reflections,
unique 2976, reflections, observed with I > 2σ(I): 2233, final R (I > 2σ(I)):
R1 ) 0.0432, wR2 ) 0.1076.
(30) Calculated for the gas phase by AM1 semiempirical calculations:
Gaussian 98: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels,
A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Salvador, P.; Dannenberg, J. J.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A. Gaussian, Inc., Pittsburgh, PA, 2001.
(24) The quantum yield for the formation of 2 was estimated using the
valerophenone actinometer.
(25) (a) Berci Filho, P.; Toscano, V. G.; Politi, M. J. J. Photochem.
Photobiol. A: Chem. 1988, 43, 51. (b) Griesbeck, A. G.; Go¨rner, H. J.
Photochem. Photobiol. A: Chem. 1999, 129, 111. (c) Go¨rner, H.; Griesbeck,
A. G.; Heinrich, T.; Kramer, W.; Oelgemo¨ller, M. Chem.sEur. J. 2001, 7,
1530.
(26) The same value of 2.4 Å has been found by X-ray analysis (see:
Orzeszko, A.; Maurin, J. K.; Melonksyta, D. Z. Naturforsch. 2001, 55b,
1035) and has been calculated by us for the gas phase by AM1 semiempirical
calculation implemented in the Gausian 98 software.
Org. Lett., Vol. 10, No. 18, 2008
3967

at δ 207.7 and 168.7 ppm, respectively. Furthermore, in the
aliphatic region of the spectrum the low-field shifted doublet
at 58.9 ppm for the CR to carbonyl clearly indicates the
1,2-aminocarbonyl relation. Isomeric 1,4-disubstituted struc-
tures show 10 ppm upfield shifted carbon resonances.
The reaction mechanism for the formation of 3 can be
explained by two parallel processes, the hydrolysis of the amide
moiety and the cyclobutanol ring opening (Scheme 2). Although
by formation of the more stabile 7-membered ring vs 9-mem-
bered ring in AN-2.
In order to demonstrate the synthetic scope of this new
domino reaction, we have performed a 10 g photolysis (in
950 mL of acetone/water 3:1) in a falling-film reactor using
a 3 kW XeCl excimer (λem ) 308 nm) radiation source.32
The precipitated solid (4.9 g analytically pure compound 2)
was collected. An additional 3.8 g was isolated from the
crude by column chromatography resulting in a total yield
of 83% of the domino product 2.
In summary, we discovered a new domino photochemi-
cal reaction sequence desymmetrizing the adamantane
skeleton by phthalimide activation. This domino reaction
yields cleanly a derivative of 2,4-methanoadamantaneben-
zazepine system, the novel 2-aza-10-hydroxyhexacyclo-
[8.7.1.11,4.04,9.011,16.012,18]nonadeca-4,6,8-triene-3-one (2),
hitherto not reported. Base hydrolysis of MAd 2 gives in
high yield the keto-substituted 1,2-adamantane derivative
of ε-amino acid 3, which is a valuable substrate for the
synthesis of various peptidomimetics.
Scheme 2. Mechanism of the Hydrolysis of 2
Acknowledgment. We thank the Ministry of Science
Education and Sports of the Republic of Croatia (Grant No.
098-0982933-2911) and Deutsche Forschungsgemeinschaft
(DFG). The support of DAAD and The Croatian Ministry
of Science, Education and Sports on a bilateral project is
also gratefully acknowledged.
MAd 2 is strained, heating in DMSO-d6 for 24 h at 100 °C
without base did not result in the opening of the cyclobutane
ring, indicating that it is not a homolytic cleavage. On the other
hand, the base-catalyzed cyclobutanol ring opening is known
to give ketone derivatives.31 In case of 2, this ring opening is
highly regioselective giving AN-1, which can be rationalized
Supporting Information Available: Physical character-
1
ization of compounds 2 and 3, H NMR spectra in CDCl3
and d6-DMSO and 13C NMR spectrum in DMSO-d6 of 2,
1H NMR and 13C NMR (DMSO-d6) of 3, crystallographic
data for 2, and UV conversion data.This material is available
free of charge via the Internet at http://pubs.acs.org.
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49, 4663. (c) Forward, P.; Hunter, W. N.; Leonard, G. A.; Palou, J.;
Walmsley, D.; Watt, C. I. F. J. Chem. Soc., Perkin Trans. 1 1993, 931. (d)
Kantrowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317.
OL801362X
(32) Griesbeck, A. G.; Bondock, S.; Maptue, N.; Oelgemo¨ller, M.
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Org. Lett., Vol. 10, No. 18, 2008