Z-Selective ring opening of vinyl oxetanes with dialkyl dithiophosphate nucleophiles

Article abstract of DOI:10.1039/c3cc46660d

Dialkyl dithiophosphates selectively ring open vinyl oxetanes in excellent yields under mild reaction conditions to form useful allylic thiophosphate products with high Z-selectivity. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc46660d

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Z-Selective ring opening of vinyl oxetanes with dialkyl
dithiophosphate nucleophiles†
Cite this: Chem. Commun., 2013,
49, 10802
B. Guo and J. T. Njardarson*
Received 31st August 2013,
Accepted 5th October 2013
DOI: 10.1039/c3cc46660d
www.rsc.org/chemcomm
Table 1 Vinyl oxetane ring opening optimization studies
Dialkyl dithiophosphates selectively ring open vinyl oxetanes in
excellent yields under mild reaction conditions to form useful
allylic thiophosphate products with high Z-selectivity.
Vinyl oxetanes are a neglected class of substrates that provide
exciting opportunities to study new ring expansions and ring
openings. We have reported two catalytic ring expansion approaches
(Fig. 1), one employing a carbene, the other a Lewis or Brønsted
acid.1 We wondered whether a dialkyl dithiophosphate could be
used to divert an acid catalyzed ring expansion pathway to a
nucleophilic ring opening pathway. Larock2 has shown that C, O,
and N-nucleophiles could be used with the help of a palladium
catalyst to ring open vinyl oxetanes. Yields are generally good and
the products are enriched in the E-olefin isomer. Although we could
not find any examples of ring expansions of vinyl oxetanes with
sulfur nucleophiles, we were encouraged by a report detailing an
oxetane ring opening with dialkyl esters of dithiophosphoric acids.3
We chose vinyl oxetane 1a as the test substrate for our
Entry (X, R)
Solvent
T (1C) t (h) Z/E ratio Yield (%)
1
2
3
4
5
6
7
8
(H, Me)
Toluene
Benzene
THF
Ether
DCE
rt
rt
rt
rt
rt
2.0 4.9 : 1
2.0 4.7 : 1
2.5 3.2 : 1
3.0 3.5 : 1
0.5 4.0 : 1
0.5 4.1 : 1
0.5 4.0 : 1
0.7 4.2 : 1
1.2 4.4 : 1
4.0 2.5 : 1
24.0 5.8 : 1
0.5 2.0 : 1
0.5 4.1 : 1
0.5 4.3 : 1
62
75
80
78
86
82
85
88
90
75
32
81
83
87
(H, Me)
(H, Me)
(H, Me)
(H, Me)
(H, Me)
(H, Me)
(H, Me)
(H, Me)
Chloroform rt
DCM
DCM
DCM
rt
0
9
ꢀ78
40
40
rt
10
11
12
13
14
(NH4, Me) DCM
(Na, Me) DCM
(TMS, Me) DCM
(H, Et)
(H, iPr)
DCM
DCM
rt
rt
reaction optimization studies (Table 1). We were delighted to learn of how efficiently and selectively dithiophosphate esters
ring opened 1a. We only observed attack at the olefin terminus
(SN20-type attack) and the resulting trisubstituted allylic thio-
phosphates were afforded as primarily Z-olefin isomers. In our
search for the optimal reaction conditions we varied the ester
group (R), counterion (X), solvent, and temperature. These
studies revealed that chlorinated solvents were most suitable,
resulting in a faster reaction and slightly higher isolated yields.
We selected dichloromethane (DCM) as our solvent of choice for
further studies. Interestingly, lowering the temperature (entries 7–9)
did not impact yield or Z/E-selectivity in a significant way, which is
why we chose to run all ensuing reactions at room temperature.
Replacement of the hydrogen with a counterion (X) resulted in
longer reactions times and less reproducible results (entries 10–12).4
Finally we looked at the size of the ester group (R). Although the
Fig. 1 Njardarson group vinyl oxetane based reactions.
results in Table 1 (entry 8 vs. entries 13–14) do not reveal a clear
preference between methyl, ethyl and isopropyl, we learned
when we investigated other substrates that the isopropyl esters
gave the best Z/E-selectivity and yields.
Department of Chemistry and Biochemistry, The University of Arizona,
1306 East University Blvd., Tucson, Arizona 85721, USA.
E-mail: njardars@email.arizona.edu
We have subjected the seventeen vinyl oxetane com-
pounds shown in Table 2 to our standard reaction conditions
† Electronic supplementary information (ESI) available: Experimental details and
spectral data for all new compounds. See DOI: 10.1039/c3cc46660d
c
10802 Chem. Commun., 2013, 49, 10802--10804
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Table 2 Vinyl oxetane ring opening scope
(1.2 equiv. diisopropyl dithiophosphate, DCM, rt). Almost all of
the substrates proceeded to form ring opening products in
excellent yields and generally high Z-selectivity. Sterics play a
key role for this new reaction, with substituents at the olefin
terminus retarding (1c and 1o) or inhibiting (1e and 1k)
nucleophilic ring opening. For substrates containing very large
2-alkyl substituents (1d, 1l and 1m) the Z-olefin selectivity was
excellent. The most drastic erosion of Z-selectivity was observed
for 1b and 1p, both of which contain an internally substituted
olefin (methyl or benzyl substitution). Vinyl oxetane substrate
1q is particularly noteworthy, as it presents an opportunity for
forming either an olefin or an allene depending on which
unsaturation the nucleophile attacks. For this substrate, the
diisopropyl dithiophosphate selectively attacked the olefin forming
an allylic thiophosphate product with high Z-selectivity.
It is interesting to contrast the orthogonal reaction outcomes
when vinyl oxetanes such as 1a are treated separately with a
diisopropyl dithiophosphate vs. diethyl phosphoric acid1b
(Scheme 1). These two nearly structurally identical reagents
are about equal when it comes to acidity (pKa),5 but differ most
significantly in terms of the relative nucleophilicity of their
respective heteroatoms (O vs. S). As a result, in one case, a
nucleophilic ring opening to form 2a proceeds, while in the
other, the vinyl oxetane cleanly ring expands to a six membered
ring (3a). Of course, as we learned from the examples presented
in Table 2, these reaction outcomes can be altered by changing
the vinyl oxetane substitution patterns. For example, nucleo-
philic attack can be completely blocked by substituting both
positions of the olefin terminus, thus forcing the dithiophosphate
to act only as an acid and afford a 3,6-dihydro-2H-pyran instead
(substrates 1e and 1k). Beyond the reactivity trends presented in
Table 2, we have also learned that alkynyl oxetanes (1s) do not
react under the normal reaction conditions. Furthermore, nucleo-
philic ring opening can also be shut down when a vinyl oxetane
substrate containing a single terminal olefin substituent and
a less reactive oxetane (mono-substituted) is employed as
exemplified by 1r.
Time (h)
0.5
Yield (%)
2/3 ratio
2 only
2 E/Z ratio
87
92
1 : 4.3
0.5
1.5
0.5
10
2 only
4.9 : 1
2 only
3 only
1 : 2.5
1 : 6.7
Z only
NA
78
95
86
0.5
0.7
0.7
0.7
90
93
92
96
2 only
2 only
2 only
2 only
1 : 5.8
1 : 7.1
1 : 7.9
1 : 7.5
0.5
8
86
90
2 only
3 only
1 : 3.8
NA
The Z-olefin products obtained from this new ring opening
reaction provided us with an opportunity to investigate the
8-membered ring S - O hopping capacity of the thiophosphate
group. Our hope was that treatment of 2a with the appropriate
0.5
0.5
91
95
2 only
2 only
Z only
Z only
0.5
2.0
80
65
2 only
1 : 4.4
1 : 5.1
5.4 : 1
0.5
0.5
48
86
2 only
2 only
1 : 1.5
1 : 8.2
Scheme 1 Nucleophilicity vs. acidity.
c
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products in excellent yields. The reaction is impacted by the
electronics and sterics of the vinyl oxetane, with electronic
stabilization of potential tertiary cation being favorable while
substitution of the olefin terminus deterring or fully inhibiting
the reaction. We have furthermore demonstrated for the first
time that these allylic thiophosphates8 can be converted to
3,6-dihydro-2H-thiopyrans upon treatment with base. Efforts
are currently underway to expand the scope of this strategy,
elucidate the exact mechanism and better understand the
limits of S - O thiophosphate hopping.
We are grateful to the National Science Foundation (CHE-1266365)
and The University of Arizona for financial support of this work.
Notes and references
1 (a) D. J. Mack, L. A. Batory and J. T. Njardarson, Org. Lett., 2012, 14,
378–381; (b) B. Guo, G. Schwarzwalder and J. T. Njardarson, Angew.
Chem., Int. Ed., 2012, 51, 5675–5678.
Scheme 2 Anionic hopping – thiopyran formation.
2 (a) R. C. Larock and S. K. Stolz-Dunn, Tetrahedron Lett., 1988, 29,
5069–5072; (b) R. C. Larock and S. K. Stolz-Dunn, Tetrahedron Lett.,
1989, 30, 3487–3490.
3 B. A. Arbuzov, O. N. Nuretdinova, F. F. Guseva, R. G. Gainullina and
L. Z. Nikonova, Bull. Acad. Sci. USSR, Div. Chem. Sci., 1973, 22,
2285–2287, translated from B. A. Arbuzov, O. N. Nuretdinova, F. F.
Guseva, R. G. Gainullina and L. Z. Nikonova, Izv. Akad. Nauk SSSR,
Ser. Khim., 1973, 2342–2345.
base would facilitate a thiophosphate transfer from 4 to 5
(Scheme 2) followed by 6-exo-tet cyclization to form 3,6-dihydro-
2H-thiopyran 6. This would represent a new approach for acces-
sing such sulfur heterocycles and a complementary one to our
vinyl nucleophile initiated approach (7 - 6),6 which proceeds via
a 6-membered ring S - O hopping step. Screening of bases,
solvents, and temperature revealed that this anionic cascade
(2a - 6) could be realized by treating 2a with sodium hydride in a
4 K, Cs, Ca, Mg, Ti, Pd, Pb, Cu(I) and Ni thiolates were also screened,
but in all cases reactions very slow and conversions low.
5 (a) W. D. Kumler and J. J. Eiler, J. Am. Chem. Soc., 1943, 65, 2355–2361;
(b) M. I. Kabachnik, T. A. Mastrukova, A. E. Shipov and T. A. Melentyeva,
Tetrahedron, 1960, 9, 10–28.
polar aprotic solvent (DMSO) at elevated temperatures (100 1C).7 6 F. Li, D. Calabrese, M. Brichacek, Y. Lin and J. T. Njardarson,
Angew. Chem., Int. Ed., 2012, 51, 1938–1941.
7 Conversion of thiophosphate 2a to thiopyran product 6 also serves as
a confirmation of the Z-olefin geometry of 2a.
These are more forcing conditions than those we required for
converting 8 to 6 (room temperature and THF), which we
contribute primarily to the more challenging 8-membered ring 8 For recent allylic thiophosphate transformations, consult: (a) A. Goswami,
J. Chem. Res., Synop., 2000, 554–555; (b) X. Han, Y. Zhang and J. Wu,
J. Am. Chem. Soc., 2010, 132, 4104–4106; (c) A. M. Lauer, F. Mahmud
and J. Wu, J. Am. Chem. Soc., 2011, 133, 9119–9123; (d) A. M. Lauer
thiophosphate hop versus a 6-membered ring.
In summary, we have developed a mild vinyl oxetane ring
opening reaction that affords Z-substituted allylic thiophosphate
and J. Wu, Org. Lett., 2012, 14, 5138–5141.
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10804 Chem. Commun., 2013, 49, 10802--10804
This journal is The Royal Society of Chemistry 2013