Thiazepine moiety-controlled regioselective rearrangements of 7-oxanorbornadiene derivatives

Article abstract of DOI:10.1039/b813371a

We have discovered thiazepine moiety-controlled regioselective skeletal rearrangements of 7-oxanorbornadiene derivatives (2, 7 and 12) with high regioselectivity and/or diastereoselectivity in the presence of Bronsted acid. The Royal Society of Chemistry.

Full text of DOI:10.1039/b813371a

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Thiazepine moiety-controlled regioselective rearrangements
of 7-oxanorbornadiene derivativeswz
Hanfeng Ding, Yiping Zhang, Weijun Yao, Duanjun Xu and Cheng Ma*
Received (in Cambridge, UK) 1st August 2008, Accepted 12th September 2008
First published as an Advance Article on the web 1st October 2008
DOI: 10.1039/b813371a
We have discovered thiazepine moiety-controlled regioselective
skeletal rearrangements of 7-oxanorbornadiene derivatives
(2, 7 and 12) with high regioselectivity and/or diastereo-
selectivity in the presence of Brønsted acid.
Due to the prevalence of thiazepine,1 oxabicyclo[2.2.1],2 and
thiazole3 cores in natural products as well as pharmaceuticals,
ring transformations of these heterocycles are of particular
interest both synthetically and theoretically.4,5 While the acid-
Fig. 1 Structures of substrates 2, 7 and 12.
induced ring-opening of 7-oxanorbornadienes (1) is known,2c,d
ring rearrangement reactions of their heterocyclic annulated
derivatives have scarcely been investigated, in a way, because
these substrates could not be easily constructed. Recently, we
have disclosed a facile synthetic route to a new polycyclic
architecture comprising a 1,4-thiazepine annulated to 1 (Fig. 1,
2, 7 and 12).6 Intrigued by their unique skeletal structures, we
have focused our efforts on the ring-opening reaction of these
compounds. Herein, we wish to describe the regioselective
Brønsted acid-induced rearrangements of thiazepine-fused
7-oxanorbornadienes (with an ester group at one of the
bridgehead positions) rendering a set of heterocyclic com-
pounds in good to excellent yields. Notably, these processes
were controlled by thiazepine moiety and, as a result, a direct
ring contraction of 1,4-thiazepine into thiazole ring was
observed for the first time under acidic conditions.7
Scheme 1 Brønsted acid-induced reactions of 2 in methanol.
Table 1 The fragmentations of 2a–k in the presence of TFAa
Entry
2
R1
R4 R5, R6
tb/h Productsc (%)
1
2a 4-BrC4H6 Ph H, H
2b 4-BrC4H6 Ph F, F
2c 4-BrC4H6 Ph CH3, CH3
2d 4-BrC4H6 Ph –(CH2)3–
2e 4-BrC4H6 Ph –O(CH2)2O–
2f 4-BrC4H6 Ph Ph, H
2g 4-BrC4H6 Ph Ph, H
2h 4-BrC4H6 Et H, H
2i 4-BrC4H6 Me H, H
3
21
3
3a + 4a, 92
3a + 4b, 82
3a + 4c, 93
3a + 4d, 95
2d
3
4
5
6
7
8
9
3
In a piloting experiment of keto-ester 2a with CF3CO2H
(TFA) in the presence of methanol, a regioselective ring-opening
reaction of 2a was observed to furnish Z-1-(thiazol-2-(3H)-
ylidene)-2-one 3a and dihydroisobenzofuran 4a as the products
(Scheme 1, Table 1, entry 1). The reaction was found not sensitive
to moisture. Stronger acids such as conc. HCl, conc. H2SO4,
pTsOH and TfOH conducted the trans-esterification reaction of
4a simultaneously, thereby to give mixtures of 4a and 5, or 5
exclusively in addition to 3a upon the reaction conditions.8
A series of keto-esters 2 involving various substituents afforded
the corresponding (Z)-3 and 4 in good to excellent yields by using
a stoichiometric amount of TFA (Scheme 1, Table 1). It
was shown that the substrates with electron-donating R5 and
R6 groups were more reactive than those having electron-
withdrawing groups. For example, 2e was transformed into 3a
0.5 3a + 4e, 97
2.5 3a + 4f, 95
2.5 3a + 4g, 95
3
3
3
3
3a + 4h, 91
3a + 4i, 92
3b + 4a, 94
3c + 4a, 84
10
11
a
2j Ph
2k t-Bu
Ph H, H
Ph H, H
Unless otherwise specified, the reaction was performed at 0.065 M
with 100 mol% of Brønsted acid in MeOH–CH2Cl2 (1 : 5) at RT.
b
c
Time for consuming the starting material. Yield of isolated
d
products 4. 20 equiv. TFA was used.
and 4e in 97% yield within 0.5 h (Table 1, entry 5), while a huge
excess of TFA (20 equiv.) was needed to convert 2b after 21 h. In
addition, the products 4h (R4 = Et) and 4i (R4 = Me) were
constructed in the Z-configuration exclusively (Table 1, entries 8
and 9).9
Given the action of methanol, compound 2a was studied as
a model substrate to react with several other alcohols in the
presence of TFA. As shown in Scheme 2, cyclohexanol,
2,2,2-trifluoroethanol, ethylene glycol, benzyl thiol and benzyl
alcohol were well tolerated in the reaction, affording the
corresponding products 6a–e in addition to 3a in 82–93%
yields, respectively.
Department of Chemistry, Zhejiang University, Hangzhou, China.
E-mail: mcorg@zju.edu.cn; Fax: 86 0571 87953375;
Tel: 86 0571 87953375
w Electronic supplementary information (ESI) available: Experimental
details, 1H and 13C NMR data for all new products. CCDC 653549
(3a), 653550 (5), 653551 (8a), 653552 (9b) and 682292 (13b). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b813371a
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Table 2 The products 9b–9h and 10 from substrates 7b–ha
Scheme 2 Reactions of 2a with various alcohols.
Scheme 3 The rearrangement of 7a to 8a and 9a.
Surprisingly, in contrast to their keto ester analogous of 2,
diester 7a gave a mixture of ionic-type product 8a and indan-1-
one 9a (ca. 10 : 1 by TLC) under the same conditions (Fig. 1,
Scheme 3). Nevertheless, 8a was found unstable in solvent and
slowly lost one molecule of TFA to yield 9a. Further experi-
ments revealed that treatment of 8a with neutral Al2O3 in
CH2Cl2 accelerated the exclusion of TFA to cleanly afford 9a
as a single product in excellent yield.
a
The reaction was performed at 0.065 M with 1.0 equiv. TFA at RT in
MeOH–CH2Cl2 (1 : 5). bYield of isolated products.
Purified by neutral Al2O3 chromatography instead silica gel,
a variety of indan-1-ones 9b–g were derived from the corre-
sponding diesters 7b–g, respectively (Scheme 3, Table 2). The
more crowded substrates led to the desired products, such as
9d and 9g, in diminished yields presumably due to the steric
hindrance in the cyclization steps (Table 2, entries 3 and 6).
Exceptionally, ester 7h bearing powerful electron-donating
groups (–OCH2O–) gave indan-1-one 9h along with dihydro-
isobenzofuran 10 in 16% yield (Table 2, entry 7). Of primary
importance, all reactions performed in this study resulted in
the selective formation of a single diastereomer.10
Scheme 4 The in situ NMR experiment of 7i.
We therefore deduced that the rearrangement reactions of 2
and 7 proceeded via a similar intermediate. Further in situ
NMR experiments of 7a and 7i demonstrated that a ring
contraction of the thiazepine moiety to a thiazole ring pro-
ceeded, at least formally, prior to the cleavage of the
oxa-bridge in current cascade procedures (Scheme 4).11
A sharply different ring-opening of keto esters 12a–c (both R3
and R4 are alkyl groups) was observed resulting in unique spiro-
cyclic products 13a–c in good yields (Scheme 5). In this case, the
heterolytic cleavage of the oxa-bridge of 12a–c did not occur as the
classical sequence induced by Brønsted acid. As for substrate 12a,
the reaction gave only trace amount of the product in the absence
of methanol; however, the yield of 13a could not be improved
when the reaction was run in large excess of H2O, although it was
shown that one molecule of H2O was added to construct the final
product. Moreover, trifluoroacetic anhydride could also give the
rearranged product 13a upon treatment with water or silica gel.
These results demonstrated that the tandem process was com-
pleted via a terminal hydrolyzation step. It is noteworthy that the
complicated thiazepinone derivative of 13b with two spirocyclic
units could be easily constructed via this strategy.
Scheme 5 Rearrangements of compounds 12a–c.
Proposed mechanisms for these Brønsted acid-triggered
regioselective rearrangements of 2, 7 and 12 are disclosed in
Scheme 6. Thus, triggered by TFA, the iminium salt A was
initially generated instead of a heterolytic cleavage of the ether
bridge in the oxabicyclic core. In path a, as for keto esters 12
(R2, R3 = alkyl), a nucleophilic addition of MeOH onto A
resulted in intermediate B, followed by an acyl cleavage to
yield oxonium C. Subsequent hydrolyzation of C afforded the
product 13 via silica gel chromatography, while for substrates
2 and 7 (R2 or R3 = aryl, in path b), the ring rearrangement of
A into D was performed.12 In the next steps, as for diester 7
(R = OMe), the isomerization of D to enol E was followed by
an intramolecular Michael addition to give F, which was
converted into indan-1-one 9 by spontaneous or neutral
Al2O3-assisted exclusion of TFA. On the other hand, for keto
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Scheme 6 Proposed mechanism for the rearrangements of 2, 7 and 12.
geometry in these groups. The solvent molecules O(1)–C(81)–C(82),
O(1W) and O(2W) have been refined with isotropic displacement
parameters due to unmodelled disorder.
esters 2 (R = aryl, alkyl), probably due to the stronger
electron-withdrawing effects of ketone group, salt D was
directly split into 3 and intermediate G, which was intercepted
by MeOH to furnish dihydroisobenzofuran 4.
1 (a) J. W. Skiles, J. T. Suh, B. E. Williams, P. R. Menard,
J. N. Barton, B. Love, H. Jones, E. S. Neiss, A. Schwab and
W. S. Mann, J. Med. Chem., 1986, 29, 784; (b) R. Malli, M. Frieden,
M. Trenker and W. F. Graier, J. Biol. Chem., 2005, 280, 12114; (c) H.
Maruenda and F. Johnson, J. Med. Chem., 1995, 38, 2145.
2 For reviews, see: (a) B. H. Lipshutz, Chem. Rev., 1986, 86, 795;
(b) M. Shipman, Contempory Org. Synth., 1995, 2, 1; (c) O. C. Kappe,
S. Murphree and A. Padwa, Tetrahedron, 1997, 53, 14179; (d) P. Chiu
and M. Lautens, Top. Curr. Chem., 1997, 190, 1–85; (e) P. Vogel, J.
Cossy, J. Plumet and O. Arjona, Tetrahedron, 1999, 55, 13521.
3 For reviews, see: (a) J. R. Lewis, Nat. Prod. Rep., 1996, 13, 435;
(b) J. V. Metzger, Thiazole and its Derivatives, John Wiley & Sons,
New York, 1979, and references therein.
In conclusion, we have discovered three unprecedented
1,4-thiazepine moiety-controlled skeletal rearrangements of
easily available 7-oxanorbornadiene derivatives induced by
Brønsted acid. The mechanistic course of these novel rearrange-
ments including the factors responsible for promoting the
pathways over the conventional sequence was explored. Further
studies into the mechanism details, scope, and synthetic appli-
cations of the current methodology are ongoing.
We are grateful to National Natural Science Foundation of
China (Grant Nos. 20672096, 20772106) for financial support.
4 For reviews, see: (a) G. Hajos, Z. Riedl and G. Kollenz,
Eur. J. Org. Chem., 2001, 3405; (b) N. Vivona, S. Buseemi, V.
Frenna and G. Gusmano, Adv. Heterocycl. Chem., 1993, 56, 49.
5 Ring-expansion of thiazole moiety into thiazepine ring in
b-lactamase inhibitors, see: (a) R. G. Micetich, S. N. Maiti, M.
Tanaka, T. Yamazaki and K. Ogawa, J. Org. Chem., 1986, 51, 853;
(b) M. Nukaga, T. Abe, A. M. Venkatesan, T. S. Mansour,
R. A. Bonomo and J. R. Knox, Biochemistry, 2003, 42, 13152.
6 (a) C. Ma, H. Ding, Y. Zhang and M. Bian, Angew. Chem., Int.
Ed., 2006, 45, 7793; (b) H. Ding, Y. Zhang, M. Bian, W. Yao and
C. Ma, J. Org. Chem., 2008, 73, 578.
7 For the oxidative condensation of some 1,4-thiazepines related
to penicillins into thiazole moiety, see: (a) N. J. Leonard and
G. Edwin Wilson, J. Am. Chem. Soc., 1964, 86, 5307; (b) F. R.
Batchelor, F. P. Doyle, J. H. C. Nayler and G. N. Rolinson,
Nature, 1959, 183, 257.
Notes and references
z Crystal data: for 3a: C15H16BrNOS; M = 338.26; T = 295(2) K;
ꢀ
triclinic; space group: P1; a = 6.952(4), b = 7.636(6), c = 15.489(11)
A, a = 78.16(3), b = 87.74(3), g = 66.38(3)1, V = 736.4(9) A3; Z = 2;
reflections collected: 7311, unique: 3345; Rint = 0.0244; R1 = 0. 0392,
wR2 = 0.0798 (observed data). For 5: C24H20O4; M = 372.40; T =
295(2) K; monoclinic; space group: P21/c; a = 11.979(4), b = 8.876(4),
c = 18.629(7) A, b = 98.484(14)1, V = 1959.1(13) A3; Z = 4;
reflections collected: 18 781, unique: 4476; Rint = 0.0285; R1 = 0.0408,
wR2 = 0.0962 (observed data). For 8a: C60H70F6N2O19S2; M =
ꢀ
1301.30; T = 293(2) K; triclinic; space group: P1; a = 14.258(3), b
= 15.677(3), c = 17.381(4) A, a = 97.49(3), b = 106.18(3), g =
115.38(3)1, V = 3228.4(19) A3; Z = 2; reflections collected: 26 071,
unique: 11 577; Rint = 0.0680; R1 = 0.1158, wR2 = 0.3182 (observed
data). Attempts to control the geometry in the disordered solvent
groups C(60), F(4)–F(9) and C(59)–O(11) failed. It was not possible to
find the hydrogen atoms on O(3W). The final R-factors and residual
electron density are high due to the poor modelling of the disordered
solvent molecules. For 9b: C29H31NO5S; M = 505.61; T = 295(2) K;
8 Compound 4a can be converted into 5 by catalytic TfOH in almost
quantitative yield after 1 h.
9 E-configuration products were not evident by 1H NMR analysis of
the crude reaction mixtures.
10 Diastereomeric products were not evident by 1H NMR analysis of
crude reaction mixtures.
ꢀ
triclinic; space group: P1; a = 9.0846(18), b = 11.400(2), c =
11 The structure of [D1]11 was determined by 2DNMR (DEPT
135, COSY, NOESY, HMQC, HMBC) and HRMS (ESI). 7a
was first converted into a pair of isomers with similar structures
to [D1]11, and that these isomers could be transformed into 9a by
neutral Al2O3 exclusively, see ESIw.
12 This process was proposed via a thioxetane intermediate. For recent
examples in metal-catalyzed reactions, see: (a) L. Peng, X. Zhang, M.
Ma and J. Wang, Angew. Chem., Int. Ed., 2007, 46, 1905; (b) G. Li
and L. Zhang, Angew. Chem., Int. Ed., 2007, 46, 5156.
13.728(3) A, a = 89.60(3), b = 77.09(3), g = 72.33(3)1, V =
1317.7(5) A3; Z = 2; reflections collected: 9633, unique: 4525; Rint
= 0.0414; R1 = 0.0452, wR2 = 0.1184 (observed data). For 13b:
C32.50H38.50BrNO5.75S; M = 647.11; T = 296(1) K; monoclinic; space
group: P21/c; a = 26.911(1), b = 10.0719(3), c = 27.669(1) A, b =
116.880(1)1, V = 6689.3(4) A3; Z = 8; reflections collected: 46 569,
unique: 11340; Rint = 0.0561; R1 = 0.0754, wR2 = 0.2164 (observed
data). The bond lengths C(58)–C(59) and C(63)–C(64) are too short
due to the impossibility of modelling disorder or restraining the
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This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 5797–5799 | 5799