Amino Azaxylylenes Photogenerated from o-Amido Imines: Photoassisted Access to Complex Spiro-Poly-Heterocycles

Article abstract of DOI:10.1002/anie.201504455

Upon irradiation, cyclic imines containing o-amido groups are shown to produce reactive intermediates, amino azaxylylenes, which undergo intramolecular cycloadditions to tethered unsaturated pendants to yield complex N,O-heterocycles having an additional spiro-connected nitrogen heterocyclic moiety. Modular assembly of the photoprecursors allows expeditious increase of the complexity of the target poly-heterocyclic scaffolds with a minimal number of experimentally simple reaction steps. The photocyclization and subsequent postphotochemical transformations are accompanied by an increase of Lovering's fsp3 factor, thus producing unprecedented three-dimensional molecular architectures, and offering extended sampling of chemical space. Rings in three dimensions: Cyclic imines containing an o-amido group undergo excited-state intramolecular proton transfer to generate amino azaxylylenes. The amino azaxylylenes undergo intramolecular cycloadditions to tethered unsaturated pendants to yield complex heterocyclic three-dimensional molecular architectures.

Full text of DOI:10.1002/anie.201504455

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201504455
German Edition: DOI: 10.1002/ange.201504455
Cycloaddition
Amino Azaxylylenes Photogenerated from o-Amido Imines:
Photoassisted Access to Complex Spiro-Poly-Heterocycles**
Olga A. Mukhina, Dmitry M. Kuznetsov, Teresa M. Cowger, and Andrei G. Kutateladze*
Abstract: Upon irradiation, cyclic imines containing o-amido
groups are shown to produce reactive intermediates, amino
azaxylylenes, which undergo intramolecular cycloadditions to
tethered unsaturated pendants to yield complex N,O-hetero-
cycles having an additional spiro-connected nitrogen hetero-
cyclic moiety. Modular assembly of the photoprecursors allows
expeditious increase of the complexity of the target poly-
heterocyclic scaffolds with a minimal number of experimen-
tally simple reaction steps. The photocyclization and subse-
quent postphotochemical transformations are accompanied by
an increase of Loveringꢀs fsp3 factor, thus producing unpre-
cedented three-dimensional molecular architectures, and offer-
ing extended sampling of chemical space.
compounds, imines have rarely been the subjects of photo-
chemical studies.[2] Such studies on imines are mostly limited
to geometrical isomerization[3] with an occasional account of
photochromism,[4] photoinduced electrocyclizations,[5] and
cycloadditions.[6] The synthetic potential of imines in photo-
chemical reactions is severely limited by the fast rotational
dissipation of excitation energy. Given that ESIPT is known
to occur in a number of hydrogen-bond donor–acceptor pairs,
especially in ortho-substituted aromatic compounds, includ-
ing imines,[7] we rationalized that such proton transfer must be
happening at least on the same time scale if not faster than the
rotational dissipation of excitation, and we attempted intra-
molecular trapping of imine-derived amino azaxylylenes. We
now report that such photoassisted intramolecular trans-
formations do indeed occur for imines, thus offering rapid
access to novel poly-heterocyclic molecular architectures.
For the initial proof of concept we performed relative
quantum yield (QY) experiments on the NMR scale, and
demonstrated that several acyclic imine photoprecurors (1a–
d; Scheme 2), which are readily available by the reaction of o-
amido benzaldehydes and primary amines, yielded both the
[4+2] and [4+4] photoproducts. The relative QY was highest
in the case of benzylimine 1a (Table 1). This could also be
more practical as benzyl is a useful protecting group which
can be readily removed.
E
arlier we demonstrated that hydroxyl azaxylylenes, gen-
erated by excited-state intramolecular proton transfer
(ESIPT) within aromatic o-aminoketones, are capable of
intramolecular cycloadditions yielding novel poly-heterocy-
clic molecular architectures possessing quinolinol (shown) or
benzazacane cores [Scheme 1; (X = O)].[1]
The preparative scale irradiation of 1a furnished the
cycloadducts 2a (45%) and 3a (24%) after column separa-
Scheme 1. Photogeneration of azaxylylenes and their intramolecular
photocyclizations.
Direct incorporation of an amino functionality into such
poly-heterocyclic scaffolds through cycloadditions of amino-
substituted azaxylylenes derived from imines [Scheme 1; (X =
N)] is appealing from a synthetic standpoint. However,
despite being isoelectronic to the thoroughly studied carbonyl
[*] Dr. O. A. Mukhina, D. M. Kuznetsov, Dr. T. M. Cowger,
Prof. Dr. A. G. Kutateladze
Scheme 2. Photogeneration of amino azaxylylenes and their intramo-
lecular photocyclizations (2b–d and 3b–d were observed by 1H NMR
spectroscopy but not isolated). DMSO=dimethylsulfoxide.
Department of Chemistry and Biochemistry
University of Denver
2190 E. Iliff Ave. Denver, CO 80208-2436 (USA)
E-mail: akutatel@du.edu
Table 1: Relative quantum yields for 1a–d.
Homepage: http://kgroup.du.edu
[**] This work is supported by the NIH (GM093930).
1a
1b
1c
1d
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504455.
f
(1.0)
0.83
0.65
0.05
11516
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11516 –11520

Angewandte
Chemie
tion (Scheme 2). It is instructive that upon heating in DMSO,
the [4+4] cycloadduct 3a undergoes the same quantitative
[4.2.1]![3.3.1] rearrangement previously observed for the
precursors possessing a cyclic imine moiety, with the goal of
accessing more complex and diverse targets. As N-acylated
isatins are known to ring-open with various nucleophiles and
dinucleophiles,[13] we modified the Schreiber and Munoz
synthetic procedure[14] for the synthesis of amidophenyl
quinoxalinones to probe whether the imine moiety in
quinoxalinones and their saturated counterparts is capable
of initiating the photoinduced proton transfer and generating
amino azaxylylenes, and to assess whether these amino
azaxylylenes are cycloaddition-competent.
aldehyde-derived products,[1f, 8] thus offering
a simple
approach to diversifying the heterocyclic core Scheme 3.
As shown in Scheme 5, the quinoxalinone photoprecur-
sors 15a–c and 16a,b were synthesized by a) N-acylating the
isatin 8 with carboxylic acids (9–11), carrying unsaturated
pendants, under EDC/DMAP coupling conditions, and
Scheme 3. The [4.2.1]![3.3.1] rearrangement of 2a.
We next examined cyclic imine photoprecursors and
established that they are photoactive as well (note that the
competing rotational relaxation channel is not available to
cyclic imines in their excited state). Cyclic imines were
expected to yield spiro-connected nitrogen heterocycles,
which have attracted considerable interest in recent years[9]
as their distinct three-dimensional structure arguably “fur-
nishes access to denser, more rigid substructures”[10] and
ostensibly allows probing vast areas of previously unexplored
chemical space. They have been targets of several creative
synthetic studies.[11] Herein we report a general method of the
cyclic-imine-based photoassisted synthesis of complex nitro-
gen poly-heterocycles containing one or two spiro-connec-
tions.
The model photoprecursor 5,[12] outfitted with a pyrroline
ring ortho to the amido moiety (see the Supporting Informa-
tion for synthetic details) was irradiated in a broadband (l =
300–400 nm) Rayonet irradiator to yield the products of [4+2]
and [4+4] cycloadditions (Scheme 4). In the photoproducts 6
Scheme 5. Fast modular assembly of quinoxalinone photoprecursors
from building blocks (cis-14b is used as a racemic mixture). EDC=[3-
(dimethylamino)propyl]carbodiimide, DMAP=N,N-(dimethylamino)-
pyridine.
b) subsequent isatin ring opening with either the diamines
13 or 14, that is, either aromatic o-phenylenediamines or
aliphatic cyclohexane- or ethylene-1,2-diamine. Such simple
and straightforward modular assembly of photoprecursors
allows for at least three diversity inputs (including the
potentially substituted isatins) and is consistent with the
philosophy of diversity-oriented synthesis.[15]
Scheme 4. Photocyclization of the pyrroline photoprecursor 5.
Quinoxalinones bearing a carbonyl group conjugated to
the imine were intentionally chosen for two reasons: 1) cyclo-
additions of photogenerated azaxylylenes with electron-rich
unsaturated pendants were expected to proceed faster,
reminiscent of inverse electron demand Diels–Alder reac-
tions, and 2) this strategically placed carbonyl group allowed
for utilization of either the oxophilic titanium- or lithium-
based Lewis acids to further polarize and activate the
azaxylylenes. We found that the photoinduced cyclization of
and 7 the upper pyrrolidine is spiro-connected to a benzaza-
cane and quinoline core, respectively. It is also easy to
recognize that the lower pyrrolidone moiety, derived from the
propanamide linker and fused to either quinoline or benza-
zacane cores, is also spiro-connected to the dihydrofuran
(DHF) fragment.
Encouraged by this result with a simple cyclic imine we
surveyed methods for rapid modular assembly of photo-
Angew. Chem. Int. Ed. 2015, 54, 11516 –11520
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11517

.
Angewandte
Communications
quinoxalinone-derived azaxylylenes in the presence of
Ti(OR)4 is accelerated by at least one order of magnitude,
and potentially offers an opportunity to utilize chiral titanium
chelators to induce enantioselective photocyclizations.[16]
The azaxylylene precursors 15 and 16 (see Table 2) have
a broad UV absorption with a maximum at around 360 nm.
Irradiations were carried out with Nichia 365 nm UV LEDs
(for experimental details see the Supporting Information) in
dichloromethane or DMSO. Optimization of irradiation
conditions revealed that addition of one equivalent of
a Lewis acid accelerates the reaction, with Ti(OiPr)4 being
particularly suitable because of its high solubility in dichloro-
methane. Irradiation proceeded smoothly, thus giving [4+4]
and [4+2] cycloaddition products. The results of irradiation of
the compounds 15a–c and 16a,b are summarized in Table 2.
syn-isomer, that is, for the anti isomers: Dd = 7.6–8.6 ppm,
while for the syn-isomers: Dd = 2.9 ppm.
The reaction is not limited to aromatic imines, as
exemplified by the ethylenediamine-based 16a and cis-1,2-
cyclohexanediamine-based precursor 16b undergoing the
same cycloaddition with moderate yields (Table 2). In the
case of 16b, both [4+4] and [4+2] products are formed as
mixtures of diastereomers.
The photoactive core of quinoxalinones is reactive toward
pyrrole-based unsaturated pendants. When pyrrole-contain-
ing carboxylic acids based on l-phenylalanine and l-ornithine
are used for the acylation of isatin, the photoprecursors 17
and 18, respectively, are obtained (Scheme 6). Both were
Table 2: Photoinduced cyclizations of the quinoxalinones 15 and 16.[a]
Photoprecursor
[4+4]
anti-[4+2]
syn-[4+2]
adduct
adduct
15a X=H, Y=
CH
15b X=F, Y=CH
19a 31%
19b 34%
19c 39%
anti-20a 18%
anti-20b 25%
anti-20c 26%
syn-20a 8%
syn-20b
11%
syn-20c –
15c X=H, Y=N
16a, (based on
14a)
16b, (based on
14b)
21a 12%
anti-22a –
syn-22a –
syn-22b –
21b, (26%+
anti-22b, (12%+
23%)[b]
15%)[b]
[a] Reaction conditions: 365 nm LED, CH2Cl2, 1–2 equiv Ti(OiPr)4. Yield
is that of the product isolated after column chromatography. [b] Dia-
stereomers resulting from stereocenters in cyclohexanediamine.
Scheme 6. Photoinduced cyclizations with pyrrole-containing amino-
acid-based pendants yield complex enantiopure nitrogen heterocycles
(yields for products isolated after two steps).
The structures of the products were unambiguously deter-
mined by X-ray analysis (5 structures). The major products
are the syn-[4++4] and anti-[4+2] adducts, where syn and anti
describe relative stereochemical arrangement of the newly
formed (benzylic) amino group and the oxygen atom of the
dihydrofuran moiety. In several cases two [4+2] isomers are
produced, with the anti adduct remaining the major product.
Stereochemistry of the major product is supported by the
13C NMR spectra: the chemical shift of the benzylic (spiro)
carbon atom is within 1 ppm (d = 59.8–60.6 ppm) for all
products regardless of stereochemistry, whereas the chemical
shift of the neighboring bridgehead carbon atom changes
from d = 51–53 ppm for the anti isomer to 57–58 ppm for the
found to be photoactive and yielded reactive synthones,
pyrrolines 23 and 24, resulting from stereoselective [4+2]
cycloaddition. These enantiopure pyrrolines are further
modified by post-photochemical transformations into sulfo-
nylamidines (25) or diazacanes (26) containing a spiro-
quinoxalinone moiety and a total of five stereogenic centers.
The yields of the products isolated after column chromatog-
raphy are modest, yet these complex enantiopure molecular
architectures are accessed in a two-step one-pot reaction from
readily available precursors.
To further probe the scope of these photoinduced intra-
molecular cyclizations we also synthesized their derivatives
with N-alkyl substituents on the quinoxalinone ring. Scheme 7
11518 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11516 –11520

Angewandte
Chemie
Table 3: Photoinduced cyclizations of N-alkylated quinoxalinones.
Photoprecursor
[4+4]
anti-[4+2]
syn-[4+2]
adduct
adduct
Alk=Me, Y=CH
35a R=R’=H
35b R=Me, R’=H
35c R=OMe, R’=H
35d R=Cl, R’=H
Alk=Bn
36a Y=CH, R=R’=H
36b Y=CH, R=R’=Me
36c Y=N, R=R’=H
38a 42%
38b 42%
38c 33%
38d 32%
anti-39a 18%
anti-39b 19%
anti-39c 13%
anti-39d 18%
syn-39a –
syn-39b[b]
syn-39c[b]
syn-39d –
40a 33%
40b 27%
40c 17%
41a’[a] 12%
anti-41b 24% syn-41b 20%
anti-41c 35% syn-41c 13%
Scheme 7. Synthesis of N-substituted quinoxalinones. (for experimen-
tal details see the Supporting Information). HATU=O-(7-azabenzotri-
azol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate,
HOAt=1-hydroxy-7-azabenzotriazole.
shows that in this case the methyl o-azidophenylglyoxalate 28,
which is readily available from isatin, was the key intermedi-
ate. While it adds two extra steps to the synthesis of the
photoprecursors, these are high-yielding steps, with the
anilines 32–34 synthesized in 0.5 gram quantities which can
be stored for subsequent modification with various unsatu-
rated substituents [Scheme 7, furanpropanoic acid (9) is
shown].
37
42 39%
anti-43 35%
syn-43
[a] Reaction conditions: 365 nm LED, CH2Cl2, 1–2 equiv Ti(OiPr)4. See
Scheme 8. [b] Observed by NMR spectroscopy and not isolated.
Table 3 summarizes the photoinduced cyclizations in the
N-substituted series. The formation of the [4+4] adduct
proceeds with complete diastereoselectivity, thus yielding
only the syn product. The pathway leading to the [4+2]
adduct is complicated in some cases by the formation of two
diastereomers, syn and anti. The second isomer (syn) proved
difficult to isolate, and was sufficiently stable only in two
cases: syn-41b and syn-41c. Similar to the N-H quinoxali-
nones, syn and anti isomers can be distinguished by 13C NMR
spectroscopy. Additionally, we were able to obtain X-ray
structures for a number of [4+2] adducts (anti-39a–d as well
as syn-41c), and they were critical for structure assignment.
Generally, the 2,3-dihydrofuran, that is, [4+2] products,
are more reactive and acid-sensitive than their [4+4] counter-
parts. In the case of 41a we observed dihydrofuran (DHF)
ring-opening and re-cyclization into the polyheterocycle 41a’,
which possesses an unprecedented piperazino-pyrrolino-
quinoline core (Scheme 8). The structure of the product is
confirmed by the agreement between the experimental and
calculated 1H and 13C NMR chemical shifts and proton spin–
spin coupling constants.[17]
In conclusion, upon irradiation of cyclic imines containing
o-amido groups reactive intermediates, amino azaxylylenes,
are produced and they are capable of intramolecular cyclo-
additions to tethered unsaturated pendants to yield complex
N,O-heterocycles with additional spiro-connected nitrogen
heterocyclic moiety. Modular assembly of photoprecursors
allows expeditious growth of the complexity of the target
poly-heterocyclic scaffolds and is achieved with a minimal
number of experimentally simple reaction steps. The photo-
Scheme 8. The DHF to pyrroline rearrangement.
cyclization and subsequent post-photochemical transforma-
tions are accompanied by the increase of Loveringꢀs fsp3
factor,[18] producing unprecedented three-dimensional molec-
ular architectures and thus offering extended sampling of
chemical space.
Keywords: cycloaddition · heterocycles · photochemistry ·
spiro compounds · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11516–11520
Angew. Chem. 2015, 127, 11678–11682
Angew. Chem. Int. Ed. 2015, 54, 11516 –11520
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11519

.
Angewandte
Communications
[9] a) C. M. Marson, Chem. Soc. Rev. 2011, 40, 5514; b) Y. Zheng,
C. M. Tice, S. B. Singh, Bioorg. Med. Chem. Lett. 2014, 24, 3673.
[10] E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257.
[11] For recent examples, see: a) M. A. Perry, R. R. Hill, S. R.
Rychnovsky, Org. Lett. 2013, 15, 2226; b) K. Kong, H. A.
Enquist, Jr., M. E. McCallum, G. M. Smith, T. Matsumaru, E.
Menhaji-Klotz, J. L. Wood, J. Am. Chem. Soc. 2013, 135, 10890;
c) S. Kotha, A. C. Deb, K. Lahiri, Synthesis 2009, 165.
[12] For experimental details see the Supporting Information.
[13] a) A. Franke, Liebigs Ann. Chem. 1982, 794; b) N. Viswanathan,
B. S. Joshi, M. A. Likhate, Proc. Indian Acad. Sci. Chem. Sci.
1984, 93, 589; c) M. Hellal, G. D. Cuny, J. Org. Chem. 2010, 75,
3465.
[1] a) O. A. Mukhina, N. N. B. Kumar, T. M. Arisco, R. A. Valiulin,
G. A. Metzel, A. G. Kutateladze, Angew. Chem. Int. Ed. 2011,
50, 9423; Angew. Chem. 2011, 123, 9595; b) N. S. Nandurkar,
N. N. B. Kumar, O. A. Mukhina, A. G. Kutateladze, ACS Comb.
Sci. 2013, 15, 73; c) N. N. B. Kumar, O. A. Mukhina, A. G.
Kutateladze, J. Am. Chem. Soc. 2013, 135, 9608; d) W. C. Cronk,
O. A. Mukhina, A. G. Kutateladze, J. Org. Chem. 2014, 79, 1235;
e) N. N. B. Kumar, D. M. Kuznetsov, A. G. Kutateladze, Org.
Lett. 2015, 17, 438; f) O. A. Mukhina, N. N. B. Kumar, T. M.
Cowger, A. G. Kutateladze, J. Org. Chem. 2014, 79, 10956;
g) W. J. Umstead, O. A. Mukhina, A. G. Kutateladze, Eur. J.
Org. Chem. 2015, 10, 2205.
[2] a) A. C. Pratt, Chem. Soc. Rev. 1977, 6, 63; b) A. Padwa, Chem.
Rev. 1977, 77, 37.
[3] a) M. E. Belowich, J. F. Stoddart, Chem. Soc. Rev. 2012, 41, 2003;
b) J.-M. Lehn, Chem. Eur. J. 2006, 12, 5910.
[14] M. Weïwer, J. Spoonamore, J. Wei, B. Guichard, N. T. Ross, K.
Masson, W. Silkworth, S. Dandapani, M. Palmer, C. A. Scherer,
A. M. Stern, S. L. Schreiber, B. Munoz, ACS Med. Chem. Lett.
2012, 3, 1034.
[4] K. Amimoto, T. Kawato, J. Photochem. Photobiol. C 2005, 6, 207.
[5] M. Austin, O. J. Egan, R. Tully, A. C. Pratt, Org. Biomol. Chem.
2007, 5, 3778.
[6] a) For a recent example, see: D. Sampedro, A. Soldevilla, P. J.
Campos, R. Ruiz, M. A. Rodrigues, J. Org. Chem. 2008, 73, 8331;
b) for a review, see: T. Nishio, in CRC Handbook of Organic
Photochemistry and Photobiology (Ed.: W. Horspool), CRC
Press, Boca Raton, FL, 1995, p. 841.
[15] “Diversity-Oriented Synthesis of Natural Product-Like Libra-
ries” M. Dow, F. Marchetti, A. Nelson in Diversity-Oriented
Synthesis: Basics and Applications in Organic Synthesis Drug
Discovery, and Chemical Biology (Ed.: A. Trabocchi), Wiley,
Hoboken, 2013.
[16] The results of the experiments with chiral TADDOL ligands will
be published elsewhere.
[17] a) A. G. Kutateladze, O. A. Mukhina, J. Org. Chem. 2015, 80,
5218; b) for the previous version of rff, see: A. G. Kutateladze,
O. A. Mukhina, J. Org. Chem. 2014, 79, 8397.
[7] F. Gao, X. Ye, H. Li, X. Zhong, Q. Wang, ChemPhysChem 2012,
13, 1313.
[8] A similar molecular skeleton was previously accessed by the
reaction of quinazolines with 1,3-bis(silyl enol ethers): a) V.
Karapetyan, S. Mkrtchyan, A. Schmidt, J. P. Gutlein, A.
Villinger, H. Reinke, H. Jiao, C. Fischer, P. Langer, Org.
Biomol. Chem. 2008, 6, 2961; b) V. Karapetyan, S. Mkrtchyan,
G. Karapetyan, A. Villinger, A. Saghiyan, T. V. Ghochikyan, P.
Langer, Helv. Chim. Acta 2011, 94, 2045.
[18] For Loveringꢀs fsp3 parameter. see: F. Lovering, H. Bikker, C.
Humblet, J. Med. Chem. 2009, 52, 6752.
Received: May 16, 2015
Revised: May 29, 2015
Published online: June 30, 2015
11520 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11516 –11520