Regioselective ring expansion of 2,4-diiminoazetidines via cleavage of C-N and C(sp3)-H bonds: Efficient construction of 2,3- dihydropyrimidinesulfonamides

Article abstract of DOI:10.1021/ja211486f

A highly regioselective base-mediated ring expansion of 2,4-diiminoazetidines via cleavage of C-N and C(sp³)-H bonds is achieved for the first time to afford efficiently 2,3- dihydropyrimidinesulfonamides. The mechanism of the ring expansion via tandem 4π electrocyclic ring-opening/1,5-H shift/6π electrocyclic ring-closing is well confirmed by the trapping experiments of two key intermediates and deuterium labeling studies.

Full text of DOI:10.1021/ja211486f

Communication
pubs.acs.org/JACS
Regioselective Ring Expansion of 2,4-Diiminoazetidines via Cleavage
of C−N and C(sp3)−H Bonds: Efficient Construction of 2,3-
Dihydropyrimidinesulfonamides
Yang Wang,† Yue Chi,† Wen-Xiong Zhang,*,†,‡ and Zhenfeng Xi*,†
†Beijing National Laboratory for Molecular Sciences, and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemisstry, Peking University, Beijing 100871, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
Scheme 1. Ring Expansion of 2,4-Diiminoazetidines via
Cleavage of C−N and C(sp3)−H Bonds
ABSTRACT: A highly regioselective base-mediated ring
expansion of 2,4-diiminoazetidines via cleavage of C−N
and C(sp3)−H bonds is achieved for the first time to
afford efficiently 2,3-dihydropyrimidinesulfonamides. The
mechanism of the ring expansion via tandem 4π
electrocyclic ring-opening/1,5-H shift/6π electrocyclic
ring-closing is well confirmed by the trapping experiments
of two key intermediates and deuterium labeling studies.
the trapping experiments of two key intermediates and
deuterium labeling studies.
Initially, 1a (R = 3-ClC6H4, R1 = Cy, R2 = 4-MeC6H4, n = 3)
za-heterocycles, such as azetidines (I) and azetidinones
was treated with different bases, such as n-BuLi, lithium
A
(II), have been extensively studied in the past three
diisopropylamide (LDA), and lithium bis(trimethylsilyl)amide
(LiHMDS), in THF at −78 °C for 1 h, and then at room
temperature for 3 h. After the reaction mixture was quenched
with water, a N-containing compound 2a was obtained in 49%,
25%, and 98% yield, respectively (Table 1). LiHMDS seemed
to be the best choice for the present reaction. The X-ray
structure of 2a revealed the product was 2,3-dihydropyrimidi-
nesulfonamide with a 6,6-spiro skeleton (Figure 1).
decades because of their great importance not only as
biologically relevant compounds but also in synthetic
applications for the construction of N-containing hetero-
cycles.1−5 The ring-opening of four-membered aza-heterocycles
is a fundamental process for the initiation of their further
synthetic transformation. Azetidines usually undergo the
cleavage of two C−N bonds; however, any of the four single
bonds of azetidinones can be broken in chemical trans-
formation. In contrast, studies on iminoazetidine chemistry are
very limited, probably due to lack of efficient synthetic
methods.6 Until recently, Xu et al reported an efficient
copper-catalyzed three-component coupling of terminal
alkynes, sulfonyl azides, and carbodiimides to give functional-
ized diiminoazetidines (III).7 Up to now, the reaction
chemistry of iminoazetidines still remains unexplored.
In the presence of 1.1 equiv of LiHMDS, a wide range of 2,4-
diiminoazetidines having a cyclic group attached to the nitrogen
atom of the azetidine ring could afford the corresponding spiro-
2,3-dihydropyrimidinesulfonamides 2a−q in good to excellent
isolated yields (Table 1). This ring expansion reaction was
compatible with halo substituents (F, Cl, Br, and I) on the
aromatic ring (2a,c−e). The substitution pattern (ortho-, meta-,
or para-) did not affect the reaction yields. Notably, 2,4-
diiminoazetidine with a cyano group on the phenyl ring (2g)
was also tolerated. Biphenyl (2h) and 6-methoxynaphthalenyl
(2i)-substituted 2,4-diiminoazetidines were both suitable
substrates for this reaction. 2,4-Diiminoazetidines having
heteroaromatic substituents afforded high yields of 2j and 2k,
respectively. The reaction of four different substituted
diiminoazetidines with LiHMDS provided smoothly 2m in
moderate yields. In addition to cyclohexyl group, five- or four-
membered ring-substituted diiminoazetidines in similar con-
ditions provided smoothly 2o and 2p, respectively. Moreover,
the reaction is not only limited to the tosyl 2,4-diiminoazeti-
dine. 2,4-Diiminoazetidine with a 4-acetamidophenylsulfonyl
We have been interested in metal-promoted reaction
chemistry of carbodiimides.8−10 Various diiminoazetidines
were prepared by the CuI-catalyzed coupling of terminal
alkynes, sulfonyl azides, and carbodiimides for our research.11
Herein, we report a highly regioselective base-mediated ring-
expansion of 2,4-diiminoazetidines to afford exclusively 2,3-
dihydropyrimidinesulfonamides in excellent yields (Scheme 1).
In this process the highly regioselective cleavage of a C−N
bond and 1,5-hydride shift are observed.12 The mechanism of
the ring expansion via tandem 4π electrocyclic ring-opening/
1,5-H shift/6π electrocyclic ring-closing is well confirmed by
Received: December 8, 2011
Published: February 3, 2012
© 2012 American Chemical Society
2926
dx.doi.org/10.1021/ja211486f | J. Am. Chem. Soc. 2012, 134, 2926−2929

Journal of the American Chemical Society
Communication
Table 1. Formation of Spiro-2,3-
a
dihydropyrimidinesulfonamides
Figure 1. ORTEP drawing of 2a with 30% thermal ellipsoids.
Hydrogen atoms except those on C2 and N1 atoms are omitted for
clarity. Selected bond length (Å): C1−N1 1.465(4), C1−N2 1.482(4),
C2−N2 1.345(4), C4−N1 1.354(4), C4−N3 1.340(4), C2−C3
1.375(4), C3−C4 1.439(5), C1−C5 1.546(5), C1−C9 1.542(4),
N3−S1 1.589(3), O1−S1 1.465(2), O2−S1 1.456(2), C20−Cl1
1.759(4).
group reacted with LiHMDS to give the desired product 2q as
well.
Summarized in Table 2 are representative results for the
synthesis of various 2,3-dihydropyrimidinesulfonamides 4a−l
showing excellent functional group compatibility as well.
Electron-withdrawing (Table 1, 2f and 2g) or electron-donating
substituents (Table 2, 4a and 4b) on the aromatic ring were
both tolerated. In addition to phenyl groups, naphthalenyl- or
benzothiophenyl-substituted diiminoazetidines also smoothly
underwent this reaction to generate the corresponding products
4c and 4d. This ring expansion reaction was applicable to a
wide variety of aliphatic substituents in 2l (Table 1) and 4e−h
(Table 2). The keto and ester groups in 4i−k survived the
present conditions. 2,4-Diiminoazetidine having two α-H atoms
adjacent to the nitrogen atom of the azetidine ring underwent
similar reaction to furnish 4l.
2,3-Dihydropyrimidinesulfonamides possessing a pyrimidine
ring and “CN2” amidine unit in this skeleton might show
unique biological activity.13 As far as we are aware, our result is
the first example of efficient preparation of well-defined 2,3-
dihydropyrimidinesulfonamides. They are a new type of N-
containing heterocyclic compounds, which cannot be accessed
by other means.
a
Conditions: 2,4-diiminoazetidines (1 mmol), LiHMDS (1.1 mmol),
THF (10 mL), unless otherwise noted. Isolated yields are given.
In order to better understand this ring expansion, isolation
and trapping experiments of four- or six-membered inter-
mediates were carried out. 2,4-Diiminoazetidine 1b was treated
with LiHMDS in THF at −78 °C for 1 h, which provided the
four-membered anionic intermediate A. We failed to isolate A
because it was only stable at low temperature and quantitatively
rearranged to six-membered anionic intermediate B when the
temperature was increased from −78 °C to room temperature.
The intermediate A was confirmed by trapping with various
electrophiles such as D2O, iodomethane, and benzoyl chloride
(Scheme 2), yielding the deuterated 2,4-diiminoazetidine 5 and
all-substituted 2,4-diiminoazetidines 6 and 7, respectively. The
D, Me, and PhCO groups were regioselectively attached to the
carbon atom of the azetidine ring. B was trapped with D2O to
quantitatively yield 2b-D. In contrast, trapping B with
iodomethane furnished the product 8. An X-ray analysis of 8
revealed the methyl group was bonded to the exocyclic
nitrogen atom.
To gain further mechanistic insight into the origin of the
hydrogen attached to the carbon of six-membered C4N2 ring,
deuterium labeling experiments were conducted (Scheme 3).
Deuterated 2,4-diiminoazetidine 1n-D was prepared (see
Supporting Information (SI)). When 1n-D was used under
the above ring-opening conditions, the deuterium was
incorporated exclusively to the C-6 position of the product
2n-D. Deuterium-labeling studies unambiguously indicate that
this hydrogen, transferred to the 6-position of 2,3-dihydropyr-
imidinesulfonamides, originates from the α-hydrogen adjoining
to the nitrogen atom of the azetidine ring.
Based on the above observations, a proposed mechanism is
shown in Scheme 4. Reaction of diiminoazetidine with
2927
dx.doi.org/10.1021/ja211486f | J. Am. Chem. Soc. 2012, 134, 2926−2929

Journal of the American Chemical Society
Communication
a
Table 2. Formation of 2,3-Dihydropyrimidinesulfonamides
Scheme 3. Deuterium Labeling Studies
Scheme 4. A Possible Mechanism
This is in agreement with the bond length of the corresponding
C−N bonds. The alkylimino C−N bond (1.427 Å) is much
longer than the sulfonylimino C−N bond (1.358 Å) in 1h (see
SI). C is then converted into intermediate D via 1,5-H shift.
The concurrent 6π electrocyclic ring-closing of D affords the
final products after quenching.
In summary, a highly regioselective base-mediated ring
expansion of 2,4-diiminoazetidines via cleavage of C−N and
C(sp3)−H bonds has been achieved to afford exclusively 2,3-
dihydropyrimidinesulfonamides in excellent yields. The mech-
anism involves tandem 4π electrocyclic ring-opening/1,5-H
shift/6π electrocyclic ring-closing, which is confirmed by the
trapping experiments of two key intermediates and deuterium
labeling experiments.
a
Conditions: 2,4-diiminoazetidines (1 mmol), LiHMDS (1.1 mmol),
THF (10 mL), unless otherwise noted. Isolated yields are given.
Scheme 2. Trapping Experiments of Intermediates A and B
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, X-ray data for 1h, 2a, and 8 (CIF), and
NMR spectra of all new products. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
wx_zhang@pku.edu.cn; zfxi@pku.edu.cn
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation of
China, Key Project of International Cooperation of NSFC
(20920102030), and the “973” program from National Basic
Research Program of China (2011CB808601 and
2012CB821600). We also thank Prof. Pixu Li of Soochow
University and Prof. Zhang-Jie Shi of Peking University for
useful discussion.
LiHMDS forms the anionic species A or A′ with the cleavage of
two potential C−N bonds (a or b). In fact, only the cleavage
C−N bond (a) was observed to evolve into intermediate C via
4π electrocyclic ring-opening. The highly regioselective C−N
cleavage is probably because the alkylimino C−N single bond
(a) is weaker than the sulfonylimino C−N single bond (b), due
to the strong electron-withdrawing nature of the sulfonyl group.
REFERENCES
■
(1) For reviews of azetidines, see: (a) Abbaspour Tehrani, K.; De
Kimpe, N. Curr. Org. Chem. 2009, 13, 854. (b) Couty, F.; Evano, G.
Synlett 2009, 3053. (c) Singh, G. S.; D’hooghe, M.; De Kimpe, N. In
2928
dx.doi.org/10.1021/ja211486f | J. Am. Chem. Soc. 2012, 134, 2926−2929

Journal of the American Chemical Society
Communication
Comprehensive Heterocyclic Chemistry III; Katritzky, A., Ramsden, C.,
Scriven, E., Taylor, R., Eds.; Elsevier: Oxford, 2008; Vol. 2, p 1.
(d) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988.
(e) Ferraris, D.; Belyakov, S.; Li, W.; Oliver, E.; Ko, Y. S.; Calvin, D.;
Lautar, S.; Thomas, B.; Rojas, C. Curr. Top. Med. Chem. 2007, 7, 597.
(f) Couty, F.; Evano, G. Org. Prep. Proced. Int 2006, 38, 427. (g) De
Kimpe, N. In Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.;
Elsevier: Oxford, 1996; Vol. 1B, p 507. (h) Cromwell, N. H.; Phillips,
B. Chem. Rev. 1979, 79, 331.
(2) For reviews of azetidinones, see: (a) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Rev. 2007, 107, 4437. (b) Dejaegher, Y.;
Kuz′menok, N. M.; Zvonok, A. M.; De Kimpe, N. Chem. Rev. 2002,
102, 29. (c) Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226.
(3) Selected examples for azetidines: (a) Denis, J.-B.; Masson, G.;
Retailleau, P.; Zhu, J. Angew. Chem., Int. Ed. 2011, 50, 5356.
(b) Shindoh, N.; Kitaura, K.; Takemoto, Y.; Takasu, K. J. Am. Chem.
Soc. 2011, 133, 8470. (c) Alcaide, B.; Almendros, P.; Luna, A.; Torres,
M. R. Adv. Synth. Catal. 2010, 352, 621. (d) Feula, A.; Male, L.;
Fossey, J. S. Org. Lett. 2010, 12, 5044. (e) Shindoh, N.; Takemoto, Y.;
Takasu, K. Chem. Eur. J. 2009, 15, 7026. (f) Ungureanu, I.; Klotz, P.;
Schoenfelder, A.; Mann, A. Chem. Commun. 2001, 958.
(4) Selected examples for azetidinones: (a) Li, G.-Q.; Li, Y.; Dai, L.-
X.; You, S.-L. Org. Lett. 2007, 9, 3519. (b) Zhao, L.; Li, C.-J. Chem.
Asian J. 2006, 1−2, 203. (c) Vargas-Sanchez, M.; Couty, F.; Evano, G.;
Prim, D.; Marrot, J. Org. Lett. 2005, 7, 5861. (d) Alcaide, B.;
Almendros, P.; Cabrero, G.; Ruiz, M. P. Org. Lett. 2005, 7, 3981.
(e) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572.
(f) Durst, T.; Elzen, R. V. D.; LeBelle, M. J. J. Am. Chem. Soc. 1972, 94,
9261.
(5) For biological activity of azetidines or azetidinones, see:
(a) Clader, J. W. Curr. Top. Med. Chem. 2005, 5, 243. (b) Setti, E.
L.; Micetich, R. G. Curr. Med. Chem. 1998, 5, 101. (c) The Organic
Chemistry of β-Lactams; Georg, G. I., Ed.; VCH: New York, 1993.
(d) Neuhaus, F. C.; Georgeopapadakou, N. H. In Emerging Targets in
Antibacterial and Antifungal Chemoterapy; Sutcliffe, J.,
Georgeopapadakou, N. H., Eds.; Chapman and Hall: New York, 1992.
(6) For the synthesis of diiminoazetidines, see: (a) Chen, C. T.;
Chan, Y. S.; Tzeng, Y. R.; Chen, M. T. Dalton Trans. 2004, 2691.
(b) Schaffer, P.; Morel, P.; Britten, J. F.; Valliant, J. F. Inorg. Chem.
2002, 41, 6493. (c) Marchand, E.; Morel, G.; Sinbandhit, S. Eur. J. Org.
Chem. 1999, 1729. (d) Aumann, R.; Heinen, H. Chem. Ber. 1986, 119,
2005, 127, 16788. (i) Ong, T.-G.; Yap, G. P. A; Richeson, D. S. J. Am.
Chem. Soc. 2003, 125, 8100.
(11) Diiminoazetidines 1a−q and 3a−l were prepared by Xu’s
procedure (ref 7a and eq 1). 1b−q and 3a−l were new compounds. In
addition to symmetric carbodiimides R1NCNR3 (R1 = R3 = Cy,
t
iPr), asymmetric carbodiimides BuNCNR3 (R3 = Cy, Et), and
PhNCNR3 (R3 = Cy, cyclopentyl, and cyclobutyl) were also
appropriate substrates for the preparation of diiminoazetidines, in
which R3 group (R3 = Cy, Et, cyclopentyl, and cyclobutyl) was
regioselectively attached on the nitrogen atom of the azetidine ring.
Furthermore, 4-acetamidophenylsulfonyl azide could be utilized to
yield the desired 1q. See SI for more details.
(12) (a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068. (b) Yoo, W.-J.; Li, C.-J. Top. Curr. Chem. 2010, 292,
281. (c) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (d) Ren, H.;
Li, Z.; Knochel, P. Chem. Asian J. 2007, 2, 416. (e) Deng, K.; Bensari,
A.; Cohen, T. J. Am. Chem. Soc. 2002, 124, 12106.
́ ́ ́
(13) (a) Wittine, K.; Benci, K.; Pavelic, S. K.; Pavelic, K.; Bratulic, S.;
Hock, K.; Balzarini, J.; Mintas, M. Med. Chem. Res. 2011, 20, 280.
̌
(b) Noll, S.; Kralj, M.; Suman, L.; Stephan, H.; Piantanida, I. Eur. J.
Med. Chem. 2009, 44, 1172. (c) Peng, X.; Hong, I. S.; Li, H.; Seidman,
M. M.; Greenberg, M. M. J. Am. Chem. Soc. 2008, 130, 10299.
(d) Beauchamp, L. M.; Serling, B. L.; Kelsey, J. E.; Biron, K. K.;
Collins, P.; Selway, J.; Lin, J.-C.; Schaeffer, H. J. J. Med. Chem. 1988,
31, 144.
́
2289. (e) L’abbe, G.; Sorgeloos, D.; Toppet, S. Tetrahedron Lett. 1982,
23, 2909. (f) Deyrup, J. A.; Vestling, M. M.; Hagan, W. V.; Yun, H. Y.
Tetrahedron 1969, 25, 1467.
(7) (a) Xu, X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9,
1585. See also a review: (b) Kim, S. H.; Park, S. H; Choi, J. H.;
Chang, S. Chem. Asian J. 2011, 6, 2618.
(8) Selected reviews of carbodiimide chemistry: (a) Nishiura, M.;
Hou, Z. Bull. Chem. Soc. Jpn. 2010, 83, 595. (b) Suzuki, T.; Zhang, W.-
X.; Nishiura, M.; Hou, Z. J. Synth. Org. Chem. Jpn. 2009, 67, 451.
(c) Shen, H.; Xie, Z. J. Organomet. Chem. 2009, 694, 1652. (d) Zhang,
W.-X.; Hou, Z. Org. Biomol. Chem. 2008, 6, 1720. (e) Edelmann, F. T.
Adv. Organomet. Chem. 2008, 57, 183. (f) Williams, A.; Ibrahim, I. T.
Chem. Rev. 1981, 81, 589.
(9) (a) Wang, Y.; Zhang, W.-X.; Wang, Z.; Xi, Z. Angew. Chem., Int.
Ed. 2011, 50, 8122. (b) Li, D.; Wang, Y.; Zhang, W.-X.; Zhang, S.;
Guang, J.; Xi, Z. Organometallics 2011, 30, 5278. (c) Li, D.; Guang, J.;
Zhang, W.-X.; Wang, Y.; Xi, Z. Org. Biomol. Chem. 2010, 8, 1816.
(d) Wang, Z.; Wang, Y.; Zhang, W.-X.; Hou, Z.; Xi, Z. J. Am. Chem.
Soc. 2009, 131, 15108. (e) Zhang, W.-X.; Li, D.; Wang, Z.; Xi, Z.
Organometallics 2009, 28, 882.
(10) (a) Zhang, W.-X.; Nishiura, M.; Mashiko, T.; Hou, Z. Chem.
Eur. J. 2008, 14, 2167. (b) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2008,
130, 3262. (c) Xu, X.; Gao, J.; Cheng, D.; Li, J.; Qiang, G.; Guo, H.
Adv. Synth. Catal. 2008, 350, 61. (d) Volonterio, A.; Zanda, M. J. Org.
Chem. 2008, 73, 7486. (e) Zhang, W.-X.; Nishiura, M.; Hou, Z. Chem.
Eur. J. 2007, 13, 4037. (f) Zhang, W.-X.; Nishiura, M.; Hou, Z. Chem.
Commun. 2006, 3812. (g) Zhang, W.-X.; Nishiura, M.; Hou, Z. Synlett
2006, 1213. (h) Zhang, W.-X.; Nishiura, M.; Hou, Z. J. Am. Chem. Soc.
2929
dx.doi.org/10.1021/ja211486f | J. Am. Chem. Soc. 2012, 134, 2926−2929