Transannular anti-Michael addition: formation of 4H-pyrazolo[5,1-c]thiazines

Article abstract of DOI:10.1016/j.tetlet.2006.09.015

The reaction of 2-(diphenylmethylene)thietan-3-one (2) with 1,2,4,5-tetrazines (3a-c) in KOH/MeOH/THF gives 4H-pyrazolo[5,1-c]thiazines (7a-c). This novel condensation reaction proceeds via the intermediacy of an 8-(diphenylmethylene)-2H-1,4,5-thiadiazocin-7(8H)-one (5), which undergoes a multi-step rearrangement including a rare anti-Michael addition.

Full text of DOI:10.1016/j.tetlet.2006.09.015

Tetrahedron Letters 47 (2006) 7893–7896
Transannular anti-Michael addition: formation of
4H-pyrazolo[5,1-c]thiazines
a
a
b
˚
Yat Fan Suen, Hakon Hope, Michael H. Nantz,
Makhluf J. Haddadinc and Mark J. Kurtha,*
aDepartment of Chemistry, University of California, Davis, CA 95616, USA
bDepartment of Chemistry, University of Louisville, Louisville, KY 40292, USA
cDepartment of Chemistry, American University of Beirut, Beirut, Lebanon
Received 16 August 2006; revised 31 August 2006; accepted 1 September 2006
Available online 25 September 2006
M.J.H. dedicates this work to Dr. Mary Kasparian for her distinguished career of chemistry teaching and high standards
at the American University of Beirut
Abstract—The reaction of 2-(diphenylmethylene)thietan-3-one (2) with 1,2,4,5-tetrazines (3a–c) in KOH/MeOH/THF gives 4H-pyr-
azolo[5,1-c]thiazines (7a–c). This novel condensation reaction proceeds via the intermediacy of an 8-(diphenylmethylene)-2H-1,4,5-
thiadiazocin-7(8H)-one (5), which undergoes a multi-step rearrangement including a rare anti-Michael addition.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The synthesis of multiply-substituted pyrazoles has
received considerable attention because of their diverse
applications in both the pharmaceutical and the agro-
chemical industries.1 In a serendipitous way, we became
interested in the synthesis of fully substituted pyrazoles
and recently reported the finding that thietanone l re-
acts, under mild basic conditions in an alcoholic solvent,
with 1,2,4,5-tetrazines 3a–c to yield pyrazole 6a–c
(Scheme 1).2 We hypothesized that the formation of
pyrazole 6 proceeded through the ring contraction/
desulfurizaton of intermediate 5. This hypothetical 8-
benzylidene-2H-1,4,5-thiadiazocin-7(8H)-one forms in
analogy to the reaction of cyclobutanone with 3, which
under similar conditions yields isolable 1,2-diazocin-4-
ones (50 in Scheme 1).3 It is believed that this multi-step
transformation of 5 to 6 is initiated by the Michael addi-
tion of an alkoxide ion (generated from solvent;
R2 = CH3, CH2CH3, CH2CH2OH) to the benzylidenone
moiety.
the resulting 1,4,5-thiadiazcinone derivative (5) would
be stable. It was envisaged that introduction of an addi-
tional phenyl ring at the exo-cyclic double bond (e.g.,
thietanone 2) would lead to isolable analogs of 5
(R1 = C6H5) by retarding the rate of alkoxide addition
to the now more hindered Michael acceptor. The
requisite 2-(diphenylmethylene)thietan-3-one (2) was
prepared4 as outlined in Scheme 2.
In the event, reaction of 2 with 1,2,4,5-tetrazine 3a deliv-
ered a stable product consistent in molecular weight
with the targeted 1,4,5-thiadiazcinone 5a (R1 = C6H5).
However, there were a number of surprising findings
`
in the spectral data of this product vis-a-vis the antici-
pated 1,4,5-thiadiazcinone—principal among these
being the presence of an unexchangeable, sharp one pro-
1
ton singlet in its H NMR at 5.85 d in addition to the
absence of methylene protons as confirmed by the lack
of 13C NMR alkyl carbons holding protons. 1,2,4,5-
Tetrazines 3b and 3c gave similar products. Fortunately,
the product from the reaction of 2 with 3c gave X-ray
crystallographic quality crystals, which established the
product as 4H-pyrazolo[5,1-c]thiazine 7c (Fig. 1).
Based upon these insights, the purpose of this work was
to manipulate the starting thietanone in such a way that
4H-Pyrazolo[5,1-c]thiazines 7a–c are fully substituted
pyrazoles wherein a sulfur-containing heteroring occu-
pies two positions on the pyrazole ring. We conjecture
that 2H-1,4,5-thiadiazocin-7(8H)-one is indeed formed
Keywords: Anti-Michael addition; Pyrazole; 4H-Pyrazolo[5,1-c]-
thiazine.
*
Corresponding author. Tel.: +1 530 752 8192; fax: +1 530 752
8995; e-mail: mjkurth@ucdavis.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.015

7894
Y. F. Suen et al. / Tetrahedron Letters 47 (2006) 7893–7896
R1
O
O
Ar
S
N
N
O
1
1
1
2
; R = H, ; R = C6H5
R
Ar
Ar
R
N
N
N
N
ROH
KOH
5`
ROH
KOH
Ar
3a-c
R1
O
Ar
R1
Ar
O-
N
N
N
N
S
S
4a-c
5
a-c
Ar
Ar
HO
R1 = H
Ar
R1 = C6H5
Ph Ph
OH
R2
O
N
S
N
Ar
N
Figure 1. Atomic displacement ellipsoid plot (70% probability) of 7c.
N
With the exception of S5 and C6, the central, fused heterocycle is
Ar
˚
Ar
planar. S5 and C6 are 1.11 and 0.54 A out of plane, respectively.
6a-c
7a-c
a
b c
, ; Ar = p-BrC6H4, ; Ar = 2-pyridyl
; Ar = C6H5
Scheme 1. 1,4,5-Thiadiazocinones (5) ! pyrazoles (6; R1 = H) and
pyrazolo[5,1-c]thiazines (7; R1 = C6H5).
5a
7a
[
]
H+
Ph
Ph
O
Ph
Ph
O
O
8
C6H5Br, Pd/C,
Bu3N, TFA, DMF
N
Ph
O
S
Ph
:
S
N
4
N
Ph
70 ºC,15h; 70%
H
N
O
Ph
S
Ph
Ph
10
8
H+
Ph
N
N
SOCl2, pyridine
Ph
O
9
0 ºC: 64%
Scheme 3. Proposed mechanism for [5a] ! 7a.
S
2
Scheme 2. Preparation of thietan-3-one 2.
and subsequently tautomerizes to 4H-1,4,5-thiadiazo-
cin-7(8H)-one (e.g., 5a ! 8 as outlined in Scheme 3).
This enamine intermediate then undergoes a transannu-
lar anti-Michael addition to the diphenylmethylenone
moiety to give 9. The ring opening via thiolate elimina-
tion delivers 1H-pyrazol-4(5H)-one 10 and the subse-
quent intramolecular thiolate Michael addition gives
the observed 4H-pyrazolo[5,1-c]thiazine (7a). Clearly,
our switch from benzylidenone-containing 1 to diphen-
ylmethylenone-containing 2 met the initial objective of
precluding alkoxide Michael addition and subsequent
formation of pyrazole 6. However, the inherent steric
encumbrance of the diphenylmethylenone moiety drives
the conversion of, for example, [5a] to 7a, the thermo-
dynamic product of this reaction.
Figure 2. A stereoview of the preferred conformation of 4H-1,4,5-
thiadiazocin-7(8H)-one 8.
the enamino nitrogen (e.g., N4 in 8) in close proximity
to C8 and hence well positions it for a transannular
anti-Michael addition to form the pyrazolo[5,1-b]thi-
azol-7(7aH)-one] intermediate 9. The ring opening to
10 and subsequent Michael addition delivers 7. This
As illustrated in Figure 2, enamine 8 adopts a crown-like
conformation in which steric interactions between the
diphenylmethylene and carbonyl moieties are minimized
by causing the C@C and C@O to become significantly
noncoplanar. Furthermore, this conformation places

Y. F. Suen et al. / Tetrahedron Letters 47 (2006) 7893–7896
7895
J = 4.8 Hz), 8.3 (1H, d, J = 4.8 Hz), 7.8 (1H, d,
J = 8.0 Hz), 7.7 (2H, m), 7.6 (1H, d, J = 8.0 Hz), 7.4
(4H, m), 7.3–7.2 (7H, m), 7.1 (1H, m), 6.8 (1H, s). 13C
NMR (CDCl3) d 57.6, 110.4, 119.3, 122.4, 123.1,
123.7, 124.7, 128.1, 128.2, 129.8, 135.8, 136.1, 137.0,
137.5, 140.0, 141.1, 147.3, 149.4, 151.5, 153.7. X-ray
C6H5
O
C6H5 O
1) nBuLi
2) H2O
C6H5
NHR
C6H5
NHR
C4H9
12
11
Scheme 4. Anti-Michael addition to acrylamide 11.
ꢀ
data: colorless, triclinic, space group P1; a = 6.5984(3),
˚
b = 9.4762(5), c = 18.8062(10) A, a = 86.689(1), b =
3
˚
anti-Michael attack by the enamino nitrogen at C8 is, to
some extent, analogues to the recent synthesis of some
annulated pyrazoles from a cyclocondensation of aryl-
hydrazines with a-oxoketene.1a It is of relevance to point
out that anti-Michael addition examples predominantly
involve additions to triple bonds5 with anti-Michael
additions to double bonds being quite rare.6 While we
were preparing this manuscript, Suzuki and co-workers
reported another example of an anti-Michael addition
reaction to a C,C-double bond.6c Our finding which,
to our knowledge constitutes the third report of an
anti-Michael addition to a double bond, bears a close
resemblance to the reported addition of n-BuLi to enam-
ido 11 to give 12 (Scheme 4).6a
87.781(1), c = 71.694(1)ꢁ, V = 1114.27(10) A , T =
93(1) K, Z = 2; 7150 reflections; R = 0.0418 for 6006
with I > 2r(I), R = 0.0515 for all. Data collection:
Bruker SMART Apex 2 diffractometer. Solution and
refinement: SHELXS97 and SHELXL97.8
Acknowledgments
The authors would like to thank the National Science
Foundation (CHE-0614756) and the National Institutes
of General Medical Sciences (GM076151) for their sup-
port of this work. The NMR spectrometers used in this
study were funded in part by grants from the NSF
(CHE-9808183) and NIH (RR-11973).
In conclusion, we have demonstrated (i) a synthesis of
the unknown 4H-pyrazolo[5,1-c]thiazine heterocycle,
(ii) the second example of a transannular reaction
in an eight-membered S,N,N-heterocycle,7 and (iii)
discovered another example of the rare anti-Michael
addition to a C,C-double bond.
References and notes
1. (a) Peruncheralathan, S.; Khan, T. A.; Illa, H.; Junjappa,
H. J. Org. Chem. 2005, 70, 10030–10035; (b) References
cited in 1a; (c) Genin, M. J.; Biles, C.; Keiser, B. J.; Swaney,
S. M.; Tarpley, W. G.; Yagi, Y.; Romero, D. L. J. Med.
Chem. 2000, 43, 1034–1040; (d) Marala, R. B.; Brown, J.
A.; Kong, J. X.; Tracey, W. R.; Knight, D. R.; Wester, R.
T.; Sun, D.; Kennedy, S. P.; Hamanaka, E. S.; Ruggeri, R.
B.; Hill, R. J. Eur. J. Pharmacol. 2002, 451, 37–41; (e)
Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J.
S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.;
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D.
J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J.
N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert,
K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J.
Med. Chem. 1997, 40, 1347–1365.
2. Suen, Y. F.; Hope, H.; Nantz, M. H.; Haddadin, M. J.;
Kurth, M. J. J. Org. Chem. 2005, 70, 8468–8471.
3. (a) Haddadin, M. J.; Agha, B. H.; Salka, S. Tetrahedron
Lett. 1984, 54, 2577–2580; (b) Robins, L. I.; Carpenter, R.
D.; Fettinger, J. C.; Haddadin, M. J.; Tinti, D. S.; Kurth,
M. J. J. Org. Chem. 2006, 71, 2480–2485.
4. (a) Amorese, A.; Arcadi, A.; Bermocchi, E.; Cashi, S.;
Cerrini, S.; Fedeli, W.; Ortar, G. O. Tetrahedron 1989, 45,
813–828; (b) Krubsack, A. J.; Higa, T.; Slack, W. E. J. Am.
Chem. Soc. 1970, 92, 5258–5259.
5. (a) Back, T. G.; Bethell, R. J.; Parvez, M.; Wehrli, D. J.
Org. Chem. 1998, 63, 7908–7919; (b) Back, T. G.; Wehrli,
D. Tetrahedron Lett. 1995, 36, 4737–4740; (c) Gerold, A.;
Krause, N. Chem. Ber. 1994, 127, 1547–1549; (d) Rudorf,
W. D.; Schwarz, R. Synlett 1993, 369–374.
Representative procedure for 2 + 3a–c ! 7a–c: Prepara-
tion of 2,7-bis(4-bromophenyl)-4,4-diphenyl-4H-pyr-
azolo[5,1-c][1,4]thiazin-3-ol (7b). To a mixture of
thietanone 2 (45 mg, 0.18 mmol) and tetrazine 3b
(140 mg, 0.36 mmol) in THF (6 mL) was added 5%
KOH/MeOH (2 mL). The mixture was stirred for
10 min at which time TLC showed complete disappear-
ance of thietanone 2. Another three portions of thieta-
none (3 · 0.18 mmol) were added over
a 5 min
interval. The mixture was then diluted with water and
made slightly acidic with 3 N HCl (in case of the reac-
tion with 3,6-di-2-pyridyl-[1,2,4,5]tetrazine 2c, the
work-up was not made acidic) and extracted with
DCM (3·). The combined organic layer was washed
with brine, dried over Na2SO4, and evaporated to dry-
ness. Flash chromatography with 10–15% EtOAc/
hexane delivered 7b as a brown oil (114 mg, 52 %).
1
Compound 7a: (56%) IR (neat) 3527 cmꢀ1. H NMR
(CDCl3) d 7.9 (2H, br d, J = 8.4 Hz), 7.4 (18H, m), 5.9
(1H, s), 3.1 (1H, br s). 13C NMR (CDCl3) d 57.2,
103.7, 125.0, 126.8, 127.9, 128.2, 128.5, 128.8, 128.9,
129.1, 129.6, 132.1, 134.4, 135.7, 139.3, 139.9, 140.3.
1
Compound 7b: (52%) IR (neat) 3522 cmꢀ1. H NMR
6. (a) Klumpp, G. W.; Mierop, A. J. C.; Vrielink, J. J.;
Brugman, A.; Schakel, M. J. Am. Chem. Soc. 1985, 107,
6740–6742; (b) Martin, V.; Molines, H.; Wakselman, C. J.
Org. Chem. 1992, 57, 5530–5532; See Scheme 5 in: (c)
Takemura, I.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett.
2006, 47, 6677–6679.
(CDCl3) d 7.7 (2H, d, J = 8.8 Hz), 7.4–7.3 (14H, m),
7.2 (H, d, J = 8.8 Hz), 5.8 (1H, s), 3.1 (1H, br s). 13C
NMR (CDCl3) d 57.8, 104.6, 122.0, 123.0, 125.1,
128.3, 129.1, 129.2, 129.5, 130.3, 131.0, 131.5, 131.7,
133.1, 135.8, 138.1, 139.0, 140.0.
7. The first example was reported recently: Khlebnikov, A. F.;
Novikov, M. S.; Shinkevich, E. Y.; Vidovic, D. Org.
Biomol. Chem. 2005, 3, 4040–4042.
Compound 7c: (52%) IR (neat) H-bonded OH 3400–
3300 cmꢀ1 (w). 1H NMR (CDCl3) d 8.6 (1H, d,

7896
Y. F. Suen et al. / Tetrahedron Letters 47 (2006) 7893–7896
8. (a) Sheldrick, G. M., University of Go¨ttingen, Germany,
1997; (b) Crystallographic data (excluding structure
factors) for 7c have been deposited with the Cambridge
Crystallographic Data Centre as Supplementary Publica-
tion Number CCDC 617978. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, fax: +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk.