Oxidative rearrangement of spiro cyclobutane cyclic aminals: Efficient construction of bicyclic amidines

Article abstract of DOI:10.1021/ol203313n

A new rearrangement reaction of spirocyclic cyclobutane N-halo aminals is described. This process, promoted by treatment of the aminals with N-halosuccinimides (NXS, X = Br or Cl), efficiently produces bicyclic amidines by a pathway involving initial N-ha

Full text of DOI:10.1021/ol203313n

ORGANIC
LETTERS
2012
Vol. 14, No. 3
772–775
Oxidative Rearrangement of Spiro
Cyclobutane Cyclic Aminals: Efficient
Construction of Bicyclic Amidines
Kenichi Murai, Hideyuki Komatsu, Ryu Nagao, and Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita, Osaka, 565-0871, Japan
fujioka@phs.osaka-u.ac.jp
Received December 12, 2011
ABSTRACT
A new rearrangement reaction of spirocyclic cyclobutane N-halo aminals is described. This process, promoted by treatment of the aminals with
N-halosuccinimides (NXS, X = Br or Cl), efficiently produces bicyclic amidines by a pathway involving initial N-halogenation of one of the aminal
nitrogens followed by cyclobutane ring expansion through 1,2-C-to-N migration with simultaneous NꢀX bond cleavage.
Reactions involving 1,2-carbon migration to a nitrogen
center comprise an important family of synthetically useful
transformations. Noteworthy examples include the Schmidt1
and Beckmann rearrangement2 reactions, which are tradi-
tionally utilized as efficient methods to generate a wide array
of heterocyclic compounds. In these respective processes,
azide (NꢀN2) and hydroxylamine derivatives (NꢀOX,
X = H, Ts, etc.) are used as latent electrophilic nitrogen
centers at which new NꢀC bonds are formed by 1,2-carbon
migration processes. In contrast, N-halo amines have been
relatively less well explored as latent electrophilic nitrogens
in rearrangement reactions. Only a few reports exist describ-
ing rearrangement reactions that are activated by treatment
of N-chloroamines with silver salts.3 Recently, the utility of
N-chloroamines as an electrophilic nitrogen source has
attracted attention in the context of useful intramolecular
aromatic amination reactions catalyzed by various metals,
such as Ni, Cu, and Ti.4
These recentobservations havestimulatedourinterestin
exploring the potential utility of N-halo amines in rearrange-
ment reactions that can be applied to the preparation of
interesting heterocyclic compounds. In the study described
below, we uncovered a previously unreported oxidative re-
arrangement reaction of spirocyclic cyclobutane aminals,
promoted by treatment with N-halosuccinimides, that pro-
duces bicyclic amidines.
In a recent investigation,5 we explored novel one-pot
reactions of aminals, formed from aldehydes and 1,2-
diamines and promoted by treatment with NBS, that lead
to the efficient formation of imidazolines (Scheme 1(1)).5a In
this context, we envisaged that a new rearrangement process
might occur with haloaminals i that derive from spirocyclic
(1) (a) Wolff, H. Org. React. 1946, 307. (b) Koldobskii, G. I.;
Tereshchenko, G. F.; Gerasimova, E. S.; Bagal, L. I. Russ. Chem. Rev.
1971, 40, 835. (c) Koldobskii, G. I.; Ostrovskii, V. A.; Gidaspov, B. V.
Russ. Chem. Rev. 1978, 47, 1084. (d) Grecian, S.; Aube, J. Organic
Azides: Syntheses and Applications; John Wiley and Sons: New York,
2010; p 191.
(4) (a) Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598.
(b) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc.
2010, 132, 6900. (c) Barker, T. J.; Jarvo, E. R. Angew. Chem., Int. Ed.
2011, 50, 8325. For transition-metal free conditions using TMEDA, see:
(d) Hatakeyama, T.; Yoshimoto, Y.; Ghorai, S. K.; Nakamura, M. Org.
Lett. 2010, 12, 1516.
(2) (a) Donaruma, L. G.; Heldt, W. Z. Org. React. 1960, 11, 1. (b)
Gawly, R. E. Org. React. 1988, 35, 1. (c) Smith, M. B.; March, J.
Advanced Organic Chemistry, 5th ed.; John Wiley & Sons: New York,
2001; p 1415.
(3) (a) Schell, F. M.; Smith, A. M. Tetrahedron Lett. 1983, 24, 1883.
(b) Schell, F. M.; Ganguly, R. N. J. Org. Chem. 1980, 45, 4069. (c)
Gassman, P. G.; Carrasquillo, A. Tetrahedron Lett. 1971, 12, 109. (d)
Gassman, P. G. Acc. Chem. Res. 1970, 3, 26.
(5) (a) Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y.
Tetrahedron Lett. 2005, 46, 2197. (b) Fujioka, H.; Murai, K.; Kubo, O.;
Ohba, Y.; Kita, Y. Tetrahedron 2007, 63, 638. (c) Murai, K.; Morishita,
M.; Nakatani, R.; Kubo, O.; Fujioka, H.; Kita, Y. J. Org. Chem. 2007,
72, 8947. (d) Murai, K.; Morishita, M.; Nakatani, R.; Fujioka, H.; Kita,
Y. Chem. Commun. 2008, 4498. (e) Murai, K.; Takaichi, N.; Takahara,
Y.; Fukushima, S.; Fujioka, H. Synthesis 2010, 520. (f) Murai, K.
Yakugaku Zasshi 2010, 130, 1011.
r
10.1021/ol203313n
Published on Web 01/24/2012
2012 American Chemical Society

cyclobutane aminals (Scheme 1(2)). Owing to the absence of
hydrogen on the spirocyclic aminal carbon of these inter-
mediates, elimination of HBr should not be possible and, in-
stead, a rearrangement reaction involving ring strain induced
cyclobutane ring expansion by C-to-N migration might
occur to yield bicyclic amidines.6ꢀ8 A further driving force
for the 1,2-carbon migration would be provided by the neigh-
boring nitrogen, which stabilizes positive charge develop-
ment at carbon center from which 1,2-migration takes place
in a manner that is similar to the driving force for the Schmidt
reaction.
ethylenediamine (2a). Reaction of these substances in di-
chloromethane for 1 d followed by solvent removal leads
to the isolation of spirocyclic aminal 3 in nearly quanti-
tative yield. Treatment of the crude product mixture
containing 3 with NBS promotes formation of bicyclic
amidine 4a in a 93% yield (Scheme 2). When NCS is
employed in place of NBS as the halogen source, the
reaction proceeds to give a comparable yield of 4a, while
NIS promotes a lower yielding reaction. The rearrange-
ment reaction of 3 occurs spontaneously even at room
temperature and in the absence of additives, such as silver
salts.3
Scheme 1. Reactions of Aminals
Scheme 2. Test Reaction
Following this study, which demonstrates the feasibility
of the new bicyclic amidine forming rearrangement reac-
tion of N-halo intermediates generated from spirocyclic
aminals, we carried out experiments designed to explore the
substrate scope of the process. A one-pot procedure was
employed for these processes, involving initial condensation
of the cyclobutanone with the selected diamine followed by
oxidative rearrangement promoted by treatment with NBS.
As the results displayed in Table 1 demonstrate, reaction
takes place to produce a bicyclic amidine in excellent yield
when 1,2-diphenyl ethylenediamine (2a) and 2,2-dimethyl-
1,3-diaminopropane (2b) are used for spirocyclic aminal
formation. The presence of substituents at C-3 of the cyclo-
butane substrate was found to have no effect on the effi-
ciency of this process (Table 1, entries 2, 4, 6, and 7). In addi-
tion, reaction of the aminal derived from diamine 2a and
3-phenylcyclobutanone (1b) generates amidine 4b as a 3:1
mixture of diasteromers. Sterically bulky 3,3-disubstituted
cyclobutane derivatives also undergo this reaction to give the
corresponding bicyclic amidines in high yields (Table 1,
entries 3 and 5). Furthermore, substrates possessing BocN,
BnO, and TBDPSO groups also react under the NBS pro-
moted reaction conditions to produce products in equally
high yields (Table 1, entries 5ꢀ7). However, the aminal de-
rived from condensation of cyclopentanone with diamine 2a
does not undergo the rearrangement reaction under the con-
ditions. This finding suggests that ring strain present in the
cyclobutane ring serves as an important driving force for the
rearrangement process.
Bicyclic amidines are an important class of organic bases,
as is exemplified by the utilzation of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-
5-ene (DBN) in promoting a variety of synthetically useful
organic transformations.9 Existing methods for the prepara-
tion of bicyclic amidines, involving cyclization reactions of
lactam derivatives, most often require several steps and harsh
reaction conditions.10 Consequently, a new method for the
efficient preparation of these substances is an important goal.
Initial studies to explore this proposal were conducted
using the reaction of cyclobutanone (1a) with 1,2-diphenyl
(6) For a review on the reactions of cyclobutanes, see: Seiser, T.;
Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50,
7740.
(7) For our studies on the reaction of cyclobutanols with hypervalent
iodine reagents, see: (a) Fujioka, H.; Komatsu, H.; Miyoshi, A.; Murai,
K.; Kita, Y. Tetrahedron Lett. 2011, 52, 973. (b) Fujioka, H.; Komatsu,
H.; Nakamura, T.; Miyoshi, A.; Hata, K.; Ganesh, J.; Murai, K.; Kita,
Y. Chem. Commun. 2010, 46, 4133.
(8) Although cyclobutane ring is strained, the rearrangement reac-
tion of cyclobutyl amine was reported to need treatment of silver salt.
See ref 3.
(9) For examples, see: (a) Ghosh, N. Synlett 2004, 574. (b) Taylor,
J. E.; Jones, M. D.; Williams, J. M. J.; Bull, S. D. Org. Lett. 2010, 12,
5740. (c) Miura, M.; Toriyama, M.; Kawakubo, T.; Yasukawa, K.;
Takido, T.; Motohashi, S. Org. Lett. 2010, 12, 3882. (d) Price, K. E.;
ꢀ
Larrivee-Aboussafy, C.; Lillie, B. M.; McLaughlin, R. W.; Mustakis, J.;
Hettenbach, K. W.; Hawkins, J. M.; Vaidyanathan, R. Org. Lett. 2009,
11, 2003. (e) Baidya, M.; Mayr, H. Chem. Commun. 2008, 1792. (f)
Birman, V. B.; Li, X.; Han, Z. Org. Lett. 2006, 9, 37. (g) Shieh, W.-C.;
ꢁ
Dell, S.; Repic, O. J. Org. Chem. 2002, 67, 2188. (h) K. Aggarwal, V.;
Mereu, A. Chem. Commun. 1999, 2311.
(10) For synthesis of DBU and DBN type bicyclic amidines, see: (a)
Kumagai, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2004, 43, 478. (b) Ostendorf, M.; Dijkink, J.; Rutjes, F. P. J. T.;
Hiemstra, H. Eur. J. Org. Chem. 2000, 115. (c) Kotsuki, H.; Sugino,
A.; Sakai, H.; Yasuoka, H. Heterocycles 2000, 53, 2561. (d) Dijkink, J.;
Eriksen, K.; Goubitz, K.; van Zanden, M. N. A.; Hiemstra, H. Tetra-
hedron: Asymmetry 1996, 7, 515. (e) Convery, M. A.; Davis, A. P.; Dunne,
C. J.; MacKinnon, J. W. Tetrahedron Lett. 1995, 36, 4279 and ref 9f.
The reaction of aminal 5a, derived by condensation of
o-aminobenzylamine (2c) was next investigated. The reaction
of the aminal 5a is of interest because two products can
possibly be produced by a difference in the reaction course.
Specifically, 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (6a)
Org. Lett., Vol. 14, No. 3, 2012
773

Table 1. Synthesis of Bicyclic Amidinesa
Scheme 3. Possible Reactions of Aminal 5a Derived from
o-Aminobenzylamine and Cyclobutanone
6a (deoxypeganine)11 in 90% yield (Scheme 4). Impor-
tantly, the amidine 6a0 was not detected in the product
mixture. This observation suggests that the rearrangement
reaction of 5a is initiated by selective chlorination of the
more nucleophilic aliphatic amine rather than the less
nucleophilic aniline nitrogen (Scheme 3, path a). When a
5:1 mixture of diastereomeric aminals 5b is used as sub-
strate, a rearrangement reaction occurs with the same
efficiency to yield 3,4-dihydroquinazoline 6b, formed by
initial aliphatic amine chlorination. Furthermore, the
structurally interesting ring-fused pentacyclic amidine 6c
can be prepared in high yield by reaction of the aminal 5c,
arising by condensation of cyclobutanone derivative 1g
with o-aminobenzylamine. The reaction of 5c showed a
selectivity trend of this transformation: the secondary alkyl
carbon migration was substantially preferred rather than
primary alkyl carbon migration from the possible intermedi-
ate i (Scheme 4, a vs b in intermediate i).
Scheme 4. Synthesis of 3,4-Dihydroquinazolines
a 1) Conditions: 1 (1.1 equiv), 2 (1 equiv), NBS (1.1 equiv), CH2Cl2
(0.1 M). 2) Substrates: 1b, 3-phenylcyclobutanone; 1c, 3,3-diphenylcyclo-
butanone; 1d, 7-tosyl-7-azaspiro[3.5]nonan-2-one; 1e, 3-(2-(benzyloxy)ethyl)
cyclobutanone; 1f, 3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclobutanone;
2b, 2,2-dimethyl-1,3-diaminopropanes.
and 1,2,3,5-tetrahydropyrrolo[1,2-a]quinazoline (6a0) can be
produced depending on which nitrogen is more rapidly halo-
genated (Scheme 3).
Aminal 5a is readily prepared by condensation of cyclo-
butanone with o-aminobenzylamine (2c) in refluxing CHCl3
and purified by using silica gel column chromatography.
Although NBS is an ideal promoter for reactions of aminals
generated from aliphatic diamines, this halogen donor is not
suitable for reaction of 5a owing to the fact that a complex
product mixture is produced as a result of competitive aro-
matic ring bromination processes. However, NCS was found
to be an excellent oxidant for promotion of the reaction of
5a, which selectively produces the 3,4-dihydroquinazoline
Interestingly, amidine 6a can be readily transformed to
quinazolinone alkaloid, deoxyvasicinone, by oxidation with
(11) (a) Khashimov, K. N.; Telezhenetskaya, M. V.; Yususov, S. Y.
Khim. Prir. Soedin. 1969, 5, 456. For examples of biological studies, see:
(b) Doetkotte, R.; Opitz, K.; Kiianmaa, K.; Winterhoff, H. Eur. J.
ꢀ
Pharmacol. 2005, 522, 72. (c) Jaen, J. C.; Gregor, V. E.; Lee, C.; Davis,
R.; Emmerling, M. Bioorg. Med. Chem. Lett. 1996, 6, 737.
774
Org. Lett., Vol. 14, No. 3, 2012

of cyclobutane aminals represents a new strategy for the
preparation of these alkaloids.
Scheme 5. Oxidation of 3,4-Dihydroquinazoline 6a
Inconclusion, the studies described abovehaveled tothe
development of an efficient method for the synthesis of
bicyclic amidines that relies on a previously unreported
rearrangement reaction of N-halo aminals. In addition, the
biologically important dihydroquinazolinone alkaloids
were prepared in this effort. Investigations exploring the
full scope of the new rearrangement reaction and its
applications are currently underway.
KMnO412 (Scheme 5). Quinazolinone and related alkaloids
have attracted recent interest owing to their biological
activities, and a number of studies have been conducted
probing the synthesis of important members of this family.13
Thus, the route utilizing oxidative rearrangement reactions
Acknowledgment. This work was financially supported
by Grant-in-Aid for Scientific Research (B) and for Young
Scientists (B) from JSPS.
Supporting Information Available. Experimental details
and detailed spectroscopic data of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(12) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008,
130, 416.
(13) For reviews, see: (a) Connolly, D. J.; Cusack, D.; O’Sullivan,
T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153. (b) Mhaske, S. B.;
Argade, N. P. Tetrahedron 2006, 62, 9787. (c) Witt, A.; Bergman, J. Curr.
Org. Chem. 2003, 7, 659.
The authors declare no competing financial interest.
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