Oxetane ring enlargement through nucleophilic trapping of radical cations by acetonitrile

Article abstract of DOI:10.1021/ol302717s

Oxidative electron transfer cycloreversion of trans,trans-2-cyclopropyl-4- methyl-3-phenyloxetane, using triphenylthiapyrylium perchlorate as a photosensitizer, leads to distonic 1,4-radical cations; subsequent cleavage gives rise to fragmentation products (pathway a), whereas nucleophilic trapping by acetonitrile affords a ring expanded oxazine (pathway b).

Full text of DOI:10.1021/ol302717s

ORGANIC
LETTERS
2
012
Vol. 14, No. 22
700–5703
Oxetane Ring Enlargement through
Nucleophilic Trapping of Radical Cations
by Acetonitrile
5
†
†
‡
,†
Ra ꢀu l P ꢀe rez-Ruiz, Jose A. S ꢀa ez, Luis R. Domingo, M. Consuelo Jim ꢀe nez,* and
Miguel A. Miranda*
,†
Departamento de Quı´mica-Instituto de Tecnologı´a Quı ´m ica UPV-CSIC,
Universitat Polit eꢁ cnica de Val eꢁ ncia, Camino de Vera s/n, E-46022, Valencia, Spain, and
Departamento de Quı´mica Org aꢀ nica, Universidad de Valencia, Dr. Moliner 50,
E-46100 Burjassot, Valencia, Spain
mcjimene@qim.upv.es; mmiranda@qim.upv.es
Received October 2, 2012
ABSTRACT
Oxidative electron transfer cycloreversion of trans,trans-2-cyclopropyl-4-methyl-3-phenyloxetane, using triphenylthiapyrylium perchlorate as
a photosensitizer, leads to distonic 1,4-radical cations; subsequent cleavage gives rise to fragmentation products (pathway a), whereas
nucleophilic trapping by acetonitrile affords a ring expanded oxazine (pathway b).
Photocycloaddition of carbonyl compounds to alkenes
PaternoꢀB u€ chi photoreaction) provides a straightfor-
1
for organic synthesis. Cycloreversion (CR) of oxetanes
transfer (PET), a possibility that has recently attracted
considerable interest in connection with its possible involve-
ment in DNA photorepair.
Semiempirical AM1 and PM3 calculations on the
photoenzymatic repair of (6-4) DNA photoproducts by
6
photolyases point to a nonconcerted, two-step mecha-
nism for cleavage of oxetane radical cations via initial
CꢀC bond cleavage. In addition, DFT calculations at
(
ward entry to oxetanes, which are versatile building blocks
3ꢀ5
can occur through cleavage of the two bonds formed in the
photocycloaddition reaction, yielding the starting materi-
2
als or, more interestingly, the formal metathesis products.
This CR can be initiated by photosensitized electron
†
Universitat Polit ꢁe cnica de Val ꢁe ncia.
(3) (a) Sadeghian, K.; Bocola, M.; Merz, T.; Sch u€ tz, M. J. Am. Chem.
Soc. 2010, 132, 16285–16295. (b) Asgatay, S.; Petermann, C.; Harakat,
D.; Guillaume, D.; Taylor, J.-S.; Clivio, P. J. Am. Chem. Soc. 2008, 130,
12618–12619. (c) Trzcionka, J.; Lhiaubet-Vallet, V.; Paris, C.;
Belmadoui, N.; Climent, M. J.; Miranda, M. A. ChemBioChem 2007,
8, 402–407. (d) Borg, O. A.; Eriksson, L. A.; Durbeej, B. J. Phys. Chem.
A 2007, 111, 2351–2361. (f) Joseph, A.; Falvey, D. E. Photochem.
Photobiol. Sci. 2002, 1, 632. (g) Cichon, M. K.; Arnold, S.; Carell, T.
Angew. Chem., Int. Ed. 2002, 41, 767.
(4) (a) Miranda, M. A.; Izquierdo, M. A.; Galindo, F. J. Org. Chem.
2002, 67, 4138–4142. (b) Miranda, M. A.; Izquierdo, M. A. J. Am. Chem.
Soc. 2002, 124, 6532–6533. (c) Miranda, M. A.; Izquierdo, M. A.
Photochem. Photobiol. Sci. 2003, 2, 848–850.
‡
Universidad de Valencia.
1) (a) Rix, D.; Ballesteros-Garrido, R.; Zeghida, W.; Besnard, C.;
(
Lacour, J. Angew. Chem., Int. Ed. 2011, 50, 7308–7311. (b) Burkhard,
J. A.; Wuitschik, G.; Rogers-Evans, M.; Mueller, K.; Carreira, E. M.
Angew. Chem., Int. Ed. 2010, 49, 9052–9067. (c) Valiulin, R. A.; Arisco,
T. M.; Kutateladze, A. G. Org. Lett. 2010, 12, 3398–3401. (d) Loy, R. N.;
Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 2786–2787. (e) Dussault,
P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591–4593. (f)
D’Auria, M. Patern oꢁ -B u€ chi reaction. In CRC Handbook of Organic
Photochemistry and Photobiology, 3rd ed.; Griesbeck, A., Oelgem €o ller, M.,
Ghetti, F., Eds.; CRC Press: Boca Raton, FL, 2012; pp 653ꢀ682.
(2) (a) Soicke, A.; Slavov, N.; Neudoerfl, J.-M.; Schmalz, H.-G.
Synlett 2011, 2487–2490. (b) D’Auria, M.; Racioppi, R.; Viggiani, L.
Photochem. Photobiol. Sci. 2010, 9, 1134–1138. (c) Valiulin, R. A.;
Kutateladze, A. G. Org. Lett. 2009, 11, 3886–3889. (d) Bach, T. Liebigs
Ann./Recueil 1997, 1627–1634. (e) Jones, G., II; Aquadro, M. A.;
Carmody, M. A. J. Chem. Soc., Chem. Commun. 1975, 206–207.
(5) (a) Nakabayashi, K.; Kojima, J. I.; Tanabe, K.; Yasuda, M.;
Shima, K. Bull. Chem. Soc. Jpn. 1989, 62, 96–101. (b) Prakash, G.;
Falvey, D. E. J. Am. Chem. Soc. 1995, 117, 11375.
(6) Wang, Y.; Gaspar, P. P.; Taylor, J. S. J. Am. Chem. Soc. 2000,
122, 5510.
1
0.1021/ol302717s r 2012 American Chemical Society
Published on Web 10/30/2012

•
þ
Scheme 1. Analysis of the Reaction Pathways Involving CꢀC and OꢀC Bond Breaking of Oxetane Radical Cation 1 , in the Absence
ꢀ1
and in the Presence of Acetonitrile, Together with Selected UMP2/6-31G(d)/PCM(Acetonitrile) Relative Energies (in kcal mol
)
the UB3LYP/6-31G* level point to CR taking place in a
concerted but asynchronous process, where CꢀC breaking
is more advanced than OꢀC breaking at the transition
The structure of 4 was assigned as cis,trans-4-cyclopropyl-
2,6-dimethyl-5-phenyl-4H-5,6-dihydro-1,3-oxazine, on the
basis of NMR experiments (SI, pp S9ꢀS11) including
NOE measurements (SI, pp S12 and S13). These data
indicate that H , H and the CH group are within the
7
state. Experimental work on the PET CR of 2,3-diphe-
nyloxetanes with (thia)pyrylium salts are in better agree-
b
2
3
3
4
ment with an initial OꢀC cleavage.
same face of the oxazine plane (Figure 1).
2
With this background, we have undertaken an experi-
mental and theoretical investigation on the PET CR of
oxetane 1. The choice of 1, bearing a cyclopropyl group at
C , was based on several reasons: (i) replacement of H by
2
cyclopropyl in analkylcation does notresultina decreased
8
charge density on the involved carbon atom, (ii) aryl
substitution is associated, instead, with the charge deloca-
4
lization typical of benzylic cations, and (iii) anodic oxida-
tion of cyclopropylmethyl iodide to the corresponding
carbocation, followed by Ritter reaction with acetonitrile
and eventual hydrolysis, affords N-(cyclopropylmethyl)-
9
,10
acetamide as a trapping product .
The target oxetane 1 was obtained by Patern oꢁ ꢀB u€ chi
photocycloaddition of trans-β-methylstyrene (2) and cy-
clopropanecarboxaldehyde (3). Sensitized photolysis of 1
was performed in the presence of catalytic (10%) amounts
of 2,4,6-triphenylthiapyrylium perchlorate (TPTP), in
Figure 1. Structural assignment of the acetonitrile adduct 4.
NOE interactions and relevant chemical shifts.
acetonitrile/N at λ
= 350 nm (Gaussian distribution).
2
max
When the PET CR of 1 was perfomed in deuterated
acetonitrile the deuterated analog (cis,trans-4-cyclopropyl-
1
The course of the reaction was followed by GC-MS and H
NMR spectroscopy. Conversion of 1 was nearly quantita-
tive after 180 min of irradiation (see Supporting Informa-
tion, SI, p S18). Three products were found in a photo-
mixture: 2 þ 3 (35%) and a solvent adduct 4 (60%).
2-(methyl-d )-6-methyl-5-phenyl-4H-5,6-dihydro-1,3-oxazine)
3
was obtained (see SI, pp S14ꢀS17). Using benzonitrile as
solvent, the corresponding nitrile adduct was also detected
by MS (M = 291, SI, p S19).
•
þ
To disclose the nature of the TPTP excited state involved
in the PET process, quenching experiments were carried
out. Thus, the fluorescence intensity of TPTP decreased
upon addition of increasing amounts of 1 (Figure 2A).
The quenching rate constant k (S ) was obtained from the
(
7) Izquierdo, M. A.; Domingo, L. R.; Miranda, M. A. J. Phys.
Chem. A 2005, 109, 2602–2607.
8) Tremper, H. S.; Shillady, D. D. J. Am. Chem. Soc. 1969, 91, 6341–
343.
9) (a) Laurent, E.; Mison, P.; Thomalla, M. Comptes Rendus des
Seances de l’Academie des Sciences, Serie C: Sciences Chimiques 1976,
(
6
(
q
1
11
10 ꢀ1 ꢀ1
SternꢀVolmer analysis; it was found to be 2.6 ꢁ 10 M s ,
283, 601. (b) Laurent, E.; Tardivel, R. Tetrahedron Lett. 1976, 32, 2779–
2782.
(
10) (a) Bishop, R. In Comprehensive Organic Synthesis; Trost, B. M.,
(11) McNaught, A. D., Wilkinson, A., Eds. IUPAC Compendium of
Chemical Terminology, 2nd ed.; Royal Society of Chemistry: Cambridge,
1997.
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, Chapter 1.9. (b) Krimen,
L. I.; Coto, N. J. Org. React. (N. Y.) 1975, 17, 213.
Org. Lett., Vol. 14, No. 22, 2012
5701

indicating a nearly diffusion-controlled process (Figure 2A,
inset). In addition, laser flash photolysis (LFP) of TPTP
eventually, back-electron transfer from the thiopyranyl
•
þ
13
radical to 2 would lead to 2. The competitive route
(b) would involve formation of a different distonic 1,4-
radical cation with spin located in the oxygen and charge in
(
λexc = 355 nm, MeCN/N ) gave rise to the typical
2
tripletꢀtriplet absorption (Figure 2B, inset); its monitoring
at 600 nm, in the presence of 1, revealed no dynamic
quenching, although the end-of-pulse absorbance clearly
decreased with increasing concentrations of 1 (Figure 2B).
The combined fluorescence and LFP results indicate that
the reaction takes place from the singlet excited state of the
photosensitizer. This agrees well with the estimation of the
free energy changes associated with electron transfer from
both excited states (SI, p S21) using the RehmꢀWeller
C . The higher degree of charge localization in this inter-
2
mediate would favor nucleophilic attack of acetonitrile at
C , leading to the corresponding nitrilium derivative; ring
2
closure and back-electron transfer would justify formation
of the observed product 4. The absence of 5 and 6 in the
photomixture indicates that trapping of the C located
2
carbocation by acetonitrile occurs faster than C ꢀC bond
3
4
cleavage. In addition, the initial trans arrangement of
phenyland cyclopropylgroups in1isno longermaintained
in4, soC ꢀC bond rotation mustoccuralongthe reaction
12
relationship.
2
3
path.
In order to rule out the possibility that the ring expan-
sion observed under PET conditions results from the well-
1
4
known acid catalyzed process, due to the presence of
adventitious acid traces generated by partial hydrolytic
ring opening of TPTP, a series of control experiments were
performed. Thus, 1 was irradiated in deuterated acetoni-
trile for 120 min in the presence of TPTP, and the reaction
1
mixture was analyzed by H NMR. At this stage, forma-
tion of 2, 3, and 4-d was clearly observed (compare
Figures 3A and 3B). Interestingly, after an additional
3
1
20 min in the dark, no significant changes in the H NMR
1
spectrum were noticed (Figure 3C).
Figure 2. (A) Fluorescence spectra of TPTP at 0.03 mM con-
centration (λexc = 435 nm, MeCN/air) in the presence of
increasing amounts of 1; inset: SternꢀVolmer plot to obtain
k
q
(S
1
). (B) Decay traces of the TꢀT absorption of TPTP
1
Figure 3. H NMR spectra of deuterated acetonitrile solutions
(
0.06 mM) measured at 600 nm in the presence of increasing
amounts of 1: 0 mM (black), 1 mM (red), 3.5 mM (green) and
mM (blue); inset: transient absorption spectrum of TPTP
of (A) 1 (8 mM) þ TPTP (0.8 mM) before irradiation; (B) 1
5
(8 mM) þ TPTP (0.8 mM) after 120 min of irradiation at λmax
=
350 nm; and (C) 1 (8 mM) þ TPTP (0.8 mM) after 120 min of
irradiation at λmax = 350 nm plus 120 min in the dark.
(
0.06 mM) recorded 0.2 μs after the laser pulse.
The proposed PET mechanism is outlined in Scheme 1.
In principle, cleavage of C ꢀC (a) or OꢀC (b) can occur.
Conversely, when catalytic amounts of HClO were
4
2
3
2
Following pathway (a), a distonic 1,4-radical cation with
spin and charge located in C and C , respectively, would
added to a freshly prepared solution of 1 in the same
1
solvent, H NMR measurements revealed formation of
3
2
be formed. This should be favored through stabilization
of the carbocationic site by oxygen as an oxonium ion.
4-d
and a total absence of 2, 3, 5, or 6. The results of these
3
control experiments unambiguously prove that different
•
þ
Subsequent OꢀC bond cleavage would afford 2 and 3;
4
(
(
13) Izquierdo, M. A.; Miranda, M. A. Eur. J. Org. Chem. 2004, 1424.
14) Hajnal, A.; W o€ lfling, J.; Schneider, G. Collect. Czech. Chem.
(
12) Rehm, D.; Weller, A. Isr. J. Chem. 1970, 8, 259–271.
Commun. 1998, 63, 1613–1622.
5
702
Org. Lett., Vol. 14, No. 22, 2012

mechanisms operate in the PET and acid catalyzed
processes.
The PET reactions of oxetane 1 were submitted to
complete a formal cycloreversion to the starting materials
employed for the PaternoꢀB u€ chi synthesis of 1) proceeds
ꢀ
1
through a barrier of only 5.6 kcal mol . The reaction path
15
•þ
theoretical calculations at the UMP2(FC)/6-31G(d) level.
Due to the intermediacy of positively charged species,
solvent effects (acetonitrile) were considered using Tomasi’s
toward 5 þ 6, which constitutes a formal metathesis
cycloreversion, shares the starting stationary point (IN21)
with ring enlargement to oxazine 4 . From this saddle
point, the energy barrier for C ꢀC bond breaking, to give
•
þ
1
6
polarized continuum model (PCM).
The stationary points found along the potential energy
3
4
•
þ
ꢀ1
5 þ 6 through TS24, is 32.8 kcal mol , which rules out
the possibility of formal metathesis cycloreversion. In the
•
þ
surface (PES) of the OꢀC and CꢀC bond breaking of 1
are depicted in Scheme 1, together with the corresponding
relative energies. Energy profiles of selected reaction paths
can be found in Figure 4. Since energy barriers for bond
presence of acetonitrile as solvent, intermediate IN21 un-
dergoes a nucleophilic attack at C giving rise to IN22 via
2
TS22. In the energy profile, TS22 is below IN21; however,
considering the entropy contribution due the bimolecular
ꢀ
1
cleavage involving C are between 7 and 15 kcal mol
4
ꢀ
1
higher than those involving C , they will not be discussed
2
further.
nature of this step, a free energy barrier of 5.3 kcal mol is
obtained. A conformational equilibrium is established
between IN22 and IN23 before intramolecular nucleophilic
•þ
attack, which yields 4 . No transition state TS23 could
be found over the PES at UMP2(FC) level; however, this
stationary point was confirmed by using density funcional
methodogy at UB3LYP/6-31G(d)/PCM (acetonitrile)
or UM06-2X/6-31G(d)/PCM (acetonitrile) levels. Back-
electron transfer (BET) could take place from the thiapyr-
•þ
anyl radical to 4 or to IN23/IN24 to give an alkoxide,
which is an excellent nucleophile and would cyclize onto
the electron-deficient carbon of the nitrilium moiety in an
essentially barrierless process.
To further the energetic discussion, both TS12 and TS22
are below the transition states of the first step. Therefore,
the kinetic control exerted by the initial ring opening,
together with the small energy difference found between
TS11 and TS21 and the activation barrier of the process
•þ
yielding 5 þ 6 (formal metathesis), explains the experi-
mentally observed formation of the cycloreversion prod-
ucts 2 and 3, in addition to oxazine 4.
Figure 4. Relative energies of the transition states and inter-
mediates involved in the PET reactions of 1 ; inset: relative free
energy of transition state, TS22.
•þ
In summary, initial O;C bond cleavage of the oxetane
2
ring under PET conditions leads to a distonic 1,4-radical
cation, which is trapped by acetonitrile to give a ring
expanded oxazine adduct. This is a new reaction, which
formally constitutes the creation of a six-membered het-
erocyclicringfromCdC, CdO, and CtN units. In addition,
splitting of the oxetane radical cation, through stepwise
•
þ
•þ
•þ
Starting from 1 , ring splitting to give 2 þ 3 or 5
, as well as ring enlargement affording oxazine 4, takes
place via a stepwise mechanism. The initial C ꢀC or
þ
6
2
3
OꢀC bond-breaking energy barriers associated with
2
ꢀ1
cleavage of the C ;C and O;C bonds, results in a
2
TS11 and TS21 are 15.0 and 16.0 kcal mol , respectively.
Regarding the corresponding intermediates, formation of
3
4
retro-PaternoꢀB u€ chi reaction.
ꢀ
1
IN11 is slightly exothermic (ꢀ0.5 kcal mol ), while that
ꢀ
1
of IN21 is endothermic (8.0 kcal mol ). Breaking of
Acknowledgment. Financial support by the MICINN
Grants CTQ-2010-14882, CTQ-2009-13699 and JCI-2010-
•
þ
(
the OꢀC bond at IN11 yielding 2 þ 3 (which would
4
06204), from CSIC (JAEDOC 101-2011) and from Gen-
(
15) (a) Møller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618–622.
eralitat Valenciana (Grant No. GV/2012/041-20120205) is
gratefully acknowledged.
(
1
8
b) Head-Gordon, M.; Pople, J. A.; Frisch, M. J. Chem. Phys. Lett. 1988,
53, 503–506. (c) Saebø, S.; Alml o€ f, J. Chem. Phys. Lett. 1989, 154,
3–89. (d) Frisch, M. J.; Head-Gordon, M.; Pople, J. A. Chem. Phys.
Lett. 1990, 166, 275–280. (e) Frisch, M.; Head-Gordon, M.; Pople,
J. A. Chem. Phys. Lett. 1990, 166, 281–289. (f) Head-Gordon, M.; Head-
Gordon, T. Chem. Phys. Lett. 1994, 220, 122–128. (g) Ab Initio Mole-
cular Orbital Theory; Hehre, W. J., Radom, L., Schleyer, P. v. P., Pople, A. J.,
Eds.; Wiley: New York, USA, 1986.
(16) (a) Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027–2094. (b)
Quantum Chemical and Statistical Theory of Solutions-A Computational
Approach; Simkin, B. Y., Sheikhet, I., Eds.; Ellis Horwood: London, U.K.,
Supporting Information Available. Additional experi-
1
13
mental details, H and C NMR spectra(including DEPT
and NOESY); computational methods; geometry of the
stationary points (Cartesian coordinates); structures of
the transition states and intermediates involved in the PET
CR of 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
3
995. (c) Cances, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107,
032–3041. (d) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. J. Chem.
Phys. Lett. 1996, 255, 327–335. (e) Barone, V.; Cossi, M.; Tomasi, J.
J. Comput. Chem. 1998, 19, 404–417.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5703