Synthesis of 1,5-dioxocanes via the two-fold C-O bond forming nucleophilic 4 + 4-cyclodimerization of cycloprop-2-en-1-ylmethanols

Article abstract of DOI:10.1039/c5ra14077c

An efficient [4 + 4] cyclodimerization of cyclopropenemethanols operating via a two-fold strain release-driven addition of alkoxides across the double bond of cyclopropenes was investigated. This chemo- and diastereoselective transformation provided previ

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RCS Advances
COMMUNICATION
Synthesis of 1,5-Dioxocanes via the Two-Fold C-O Bond
Forming Nucleophilic 4+4-Cyclodimerization of Cycloprop-2-en-1-
ylmethanols
Received 00th January 20xx,
Accepted 00th January 20xx
a
a,b
a
a,c
DOI: 10.1039/x0xx00000x
Andrew Edwards, Trevor Bennin, Marina Rubina, and Michael Rubin*
www.rsc.org/
Abstract. An efficient [4+4] cyclodimerization of cyclopropenemethanols
operating via a two-fold strain release-driven addition of alkoxides across
the double bond of cyclopropenes was investigated. This chemo- and
diastereoselective transformation provided previously unknown 2,7-
dioxatricyclo[7.1.0.04,6]decane scaffolds.
1
2
Transition metal-catalyzed or photo-assisted 4+4-cyclodimerizat-
ions with the simultaneous formation of two new C-C bonds are
routinely used for assembly of eight-membered alicyclic comp-
ounds. However, analogous C-O bond-forming dimerization strat-
egies for the preparation of eight-membered oxygen-based heter-
ocycles remain much less explored. Nucleophilic closure of medium
size rings is generally much more challenging than their five- and
six-membered analogs due to a notable increase in ring strain
(
unfavorable enthalpic factor) and the accompanying significant loss
of conformational freedom (unfavorable entropic factor). One of
the few successful reported examples is the cyclodimerization of 2-
alkoxyoxetanes, proceeding via acid-catalyzed or photo-induced
3
4
5
reacetalization of ketals, ortho-esters, or enol ethers (Scheme 1,
eq. 1). Also, the assembly of eight-membered cyclic diesters via a
double-fold Yamaguchi esterification of 3-hydroxypropanoic acids
was employed during the total synthesis of (+)-bourgeanic lactone
Scheme 1
6
(
eq. 2). Somewhat less successful esterification under Steglich
conditions providing cyclic trimers as major products was also
7
reported. While the above examples involved carbonyl derivatives,
synthesis of the 1,5-dioxocane core via a 4+4-cyclodimerization
accompanied by the installation of two ethereal C-O bonds has not
been reported to date. Herein we demonstrate an efficient and
selective formation of the 1,5-dioxocane core via a strain release-
driven double-fold addition of alkoxides across the double bond of
cyclopropenes 3, providing access to peculiar 2,7-dioxatricyclo-
4
,6
[
7.1.0.0 ] decanes 4 (eq. 3).
Scheme 2
In our previous work on the development of practical synthetic
8
9
approaches to cyclopropyl ether and cyclopropyl amine
derivatives via the formal nucleophilic substitution of
7
8,9
cyclopropylhalides 5 (Scheme 2, eq. 4), we have shown that a
variety of alkoxides, and amides can be added across the double
bond of in situ generated cyclopropenes. It was also demonstrated
that an intramolecular version of this reaction could efficiently
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Table 1. Optimization of 4+4-cyclization of alcohol 3a
a
b
#
Base
mass, mg)
Solvent
Yield, %
dr (4a:16a)
(
(volume, mL)
THF (1)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
KOH (12)
74
70
0
99:1
99:1
-
t-BuOK (24)
KOH (12)
THF (1)
Scheme 4
THF (3)
imental to the diastereoselectivity (Table 1, entries 5-13). Reactions
performed in diethyl ether and toluene were selective, but much
less efficient (entries 14-17). No product was observed in
dichloromethane (entries 18-19), carbon tetrachloride (entries 20-
t-BuOK (24)
KOH (12)
THF (3)
0
-
DMSO (1)
DMSO (1)
DMSO (3)
DMSO (3)
DMSO (0.5)
DMF (1)
DMF (1)
DMA (1)
DMA (1)
32
75
57
78
57
36
57
36
68
60
58
28
43
0
83:17
85:15
81:19
82:18
84:16
89:11
95:5
91:9
90:10
99:1
98:2
99:1
98:2
-
t-BuOK (24)
KOH (12)
2
1), and 1,4-dioxane (entries 22-23).
t-BuOK (24)
t-BuOK (24)
KOH (12)
With the optimized procedure in hand we carried out preparative
synthesis of 4a and its 4-fluoro- (3b), 2,4-difluoro- (3c), 2-chloro-4-
fluoro- (3d), and 2-bromo-4-fluoro- (3e) substituted analogs 4b-e,
all of which were obtained in good yields (Scheme 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
t-BuOK (24)
KOH (12)
The starting cyclopropene alcohols 3 are readily available by
reduction of the corresponding 1-arylcycloprop-2-ene-1-carbox-
t-BuOK (24)
KOH (12)
Et
Et
2
O (1)
O (1)
1
2
ylates 10 (Scheme 4), which are routinely obtained by Rh-
catalyzed [2+1] cycloaddition of diazoarylacetates to trimethylsilyl-
acetylene, followed by desilylation of the corresponding silylcyclo-
t-BuOK (24)
KOH (12)
2
PhMe (1)
PhMe (1)
t-BuOK (24)
KOH (12)
13
propenes 9. Alternatively, the reduction and the protodesilylation
CH
CH
2
2
Cl
Cl
2
(1)
(1)
1
4
step can be swapped, which usually provides better yields in
DIBAL reduction (9ꢀ11), but at the expense of efficiency on
desilylation step (11ꢀ3) (Scheme 4). We proposed that desilylation
and subsequent nucleophilic addition (3ꢀ4) could be combined in a
one-pot sequence to obtain 1,5-dioxocanes directly from TMS-
protected precursor 11. To test this idea, alcohol 11a (Ar = Ph) was
subjected to the reaction conditions for 4+4-cyclodimerization
described above. Gratifyingly, the same dioxocane 4a formed as
sole isolable product in comparable yield (Table 2). Optimization of
the reaction conditions revealed similar trends as the described
above initial screening (Table 1); however, this one-pot
transformation proceeded somewhat slower, requiring 5.5 equiv. of
base (Table 2, entries 1-4) and slightly elevated temperature
t-BuOK (24)
KOH (12)
2
0
-
CCl
CCl
4
(1)
(1)
0
-
t-BuOK (24)
KOH (12)
4
0
-
1,4-dioxane (1)
1,4-dioxane (1)
0
-
2
t-BuOK (24)
0
-
a
NMR yieds. Test reactions were performed in 6.3 mg (43 μmol)
o
11
mmol scale (based on 3a) at 55 C.
b
Determined by GC analyses of crude reaction mixtures
1
0
provide 2-oxabicyclo[5.1.0]octanes 8 (Scheme 2, eq. 5).
In our
efforts toward expanding the scope of available strained substrates,
we probed the reaction of (1-phenylcycloprop-2-en-1-yl)methanol
3a) under our standard reaction conditions with t-BuOK in THF in
the presence of catalytic amount of 18-crown-6 ether (Table 1,
entry 2). Remarkably, homodimerization outcompeted addition of
(
8
(
entries 4-8) to achieve complete conversion.
-
With more easily accessed, silyl-protected alcohols 11, we tested
the external nucleophile (t-BuO ) providing a single isomer of eight-
membered cyclic ether 4a in 70% NMR yield and dr of 99:1, as the this reaction on fifteen other (1-aryl-2-silyl-cycloprop-2-en-1-
1
1
only observable product. Optimization studies proved powdered yl)methanols possessing differently substituted aryl groups (Table
KOH to be a more efficient base than t-BuOK (Table 1, entry 1). It 3). The first five examples shown in Table 3 (entries 1-5) allow for
was also found that polar, aprotic, coordinating solvents were detr-
direct comparison of the one-pot desilylation/dimerization
approach with the described above stepwise protocol (Scheme 3).
In all cases the efficiency of the processes remained essentially the
same. In the reactions of cyclopropenes 11c and 11j bearing two
fluorine substituents competitive formation of two products was
observed. These compounds were identified as diastereomers with
trans- (1R*,4R*,6S*,9S*) (for major component) and cis-
(
1R*,4S*,6R*, 9S*) configurations, respectively. For all other
examples the only isolable product was trans-2,7-dioxatricyclo-
4
,6
[
7.1.0.0 ]decane 4, which was unambiguously confirmed by single
crystal X-Ray crystallography of para-tolyl-substituted dioxocane 4g
(Figure 1, CCDC #1408273). The high trans-selectivity observed in
Scheme 3
2
| J. Name., 2012, 00, 1-3
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PleaseRd So Cn oA t da vd aj un s ct ems argins
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Table 2. Optimization of 4+4-cyclization of alcohol 11a
o
#
Base
Solvent
Temp, C
(time, h)
65 (24)
65 (24)
65 (24)
65 (24)
75 (24)
55 (24)
45 (24)
35 (24)
65 (24)
65 (24)
65 (24)
65 (24)
65 (24)
65 (72)
65 (72)
65 (72)
65 (72)
65 (24)
65 (24)
65 (72)
65 (72)
Yield,
dr
a
(
mass, mg) (1 mL)
%
(4a:16a)
98:2
98:2
98:2
98:2
97:3
98:2
98:2
-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
KOH (4.5)
KOH (9.5)
KOH (12)
KOH (24)
KOH (12)
KOH (12)
KOH (12)
KOH (12)
THF
THF
THF
THF
THF
THF
THF
THF
72
68
77
73
49
56
21
0
4
,6
Figure 1. ORTEP drawing of 2,7-dioxatricyclo[7.1.0.0 ] decane 4g
showing 50% probability amplitude displacement ellipsoids.
should be mentioned that arguments pertaining to greater
thermodynamic stability of cyclic dimer 4 vs 16, can be ruled out
since both steps (15ꢀ4) and (15ꢀ16) are irreversible (Scheme 5).
t-BuOK (24) THF
70
45
67
99:1
86:14
87:13
94:6
91:9
93:7
92:8
93:7
92:8
99:1
99:1
98:2
98:2
Thus, our experiment showed that a sample of 4a generated in
DMSO and partially enriched with cis-cyclic dimer 16a (4a:16a =
71:29), being re-subjected to the reaction conditions did not change
its composition.
0
1
2
3
4
5
6
7
8
9
0
1
KOH (12)
DMSO
t-BuOK (24) DMSO
b
KOH (12)
t-BuOK (24) DMF
KOH (12) DMF
t-BuOK (24) DMF
KOH (12) DMA
t-BuOK (24) DMA
DMF
29
b
29
b
It is also important to mention that the fate of the minor linear
intermediate, trans-14 is completely different from that of cis-15, as
it cannot undergo analogous cyclization. The cyclopropene and the
alkoxymethyl moieties in trans-14 are located away from each
other on the opposite sides of the cyclopropyl ring and, as a result,
an intermolecular nucleophilic attack takes place predominantly,
leading to linear oligomers and polymers. This bimolecular process
is much slower, and allows for accumulation of intermediate 14 at
34
b
21
54
48
59
61
71
75
KOH (12)
t-BuOK (24) Et
KOH (12)
t-BuOK (24) PhMe b
Et
2
O
2
O
PhMe
2
a
NMR yields are listed. Incomplete conversion: GC analysis
showed presence of unreacted starting material 11a. Test reactions
1
1
were performed in 9.3 mg (43 μmol) mmol scale based on 11a.
Table 3. One-pot desilylation/4+4-cyclodimerization of (1-aryl-2-
silylcycloprop-2-en-1-yl)methanols 11.
the formation of these rigid tricyclic products can be rationalized as
8
follows (Scheme 5). Initially, the intermolecular nucleophilic attack
of the primary alkoxide moiety in 12 at the double bond of the
second cyclopropene molecule can potentially provide two interm-
ediates: trans- (14) or cis-linear dimer (15), respectively. This strain
release-driven step is highly exothermic and, therefore, essentially
irreversible. Accordingly, the facial selectivity of this addition (in
this case in the absence of efficient directing groups) should be
a
#
1
2
3
4
5
6
7
8
9
1
1
1
1
1
11
Ar
4
Yield, % (dr)
11a
11b
11c
11d
11e
11f
11g
11h
11i
Ph
4a
4b
4c
4d
4e
4f
64 (98:2)
4-FC
6
H
4
59 (>99:1)
b
2,4-F
2
C
6
H
3
62 (92:8)
8
exclusively governed by steric factors. The considerably larger size
2-Cl-4-FC
2-Br-4-FC
6
H
3
79 (>99:1)
63 (>99:1)
55 (>99:1)
78 (>99:1)
69 (>99:1)
62 (>99:1)
of the aryl substituent as compared to hydroxymethyl group is,
therefore, the main reason for cis-diastereomer 15 to be formed
predominantly. The preference of the second nucleophilic attack at
diastereotopic C-1 vs C-2 in the cyclopropene moiety of 15 leads to
the highly selective formation of trans-cyclic dimer 4 with traces of
cis-dimer 16 observed. Reasons affecting the stereodifferentiation
in the intramolecular 8-exo-trig cyclization at this point are not
completely understood. It is believed that the initial pre-coord-
ination of the alkoxide moiety with potassium cation affords a more
6 3
H
1-naphthyl
4-MeC
2-Cl-6-FC
2-ClC
2,3-F
6
H
4
4g
4h
4i
6 3
H
6 4
H
b
1
2
3
4
5
6
11j
2
C
6
H
3
4j
57 (88:12)
83 (>99:1)
67 (>99:1)
65 (99:1)
70 (>99:1)
32 (98:2)
11k
11l
3-BrC
4-BrC
6
H
H
4
4
6
4k
4l
6
11m
11n
11o
2,4-Cl
3-CF
2-Cl-4,5-F
2
C
H
3
4m
4n
4o
2
favorable transition state leading to C -symmetric product 4. This
3 6 4
C H
hypothesis is supported by experiments carried out in coordinating
aprotic solvents (DMSO, DMF, DMA), which provided notably lower
1
2
C
6
H
2
a
Isolated yields of purified products are provided. Diastereomeric
diastereoselectivities (Tables 1,2). Computational investigations ratios were determined by GC analyses of crude reaction mixtures.
Notation >99:1 indicates that minor diasereomer was below the
detection limit. Diastereomeric ratios were determined by H NMR
of crude reaction mixtures.
that could support or rule out this hypothesis are currently
underway in our laboratories and will be reported in due course. It
b
1
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Fund for Basic Research (grant #15-03-02661) and NSF REU
program grant #CHE-1263259 for student support (TB). Support for
the NMR instrumentation was provided by NIH Shared Instrument-
ation Grant #S10RR024664 and NSF Major Research Instrument-
ation Grant #0320648.
Notes and references
1
For review, see: (a) J. Montgomery, Sci. Synth., 2002, 1, 11.
See also: (b) R. Shintani, T. Tsuji, S. Park and T. Hayashi,
Chem. Commun., 2010, 46, 1697; (c) P. H. Lee, K. Lee and Y.
Kang, J. Am. Chem. Soc., 2006, 128, 1139; (d) P. H. Lee and K.
Lee, Angew. Chem., Int. Ed., 2005, 44, 3253; (e) M. A.
ElAmrani, I. Suisse, N. Knouzi and A. Mortreux, Tetrahedron
Lett., 1995, 36, 5011; (f) A. Bendayan, H. Masotti; G. Peiffer,
C. Siv and A. Archavlis, J. Organomet. Chem., 1993, 444, 41;
(
g) K. Masuda, K. Nakano, T. Fukahori, H. Nagashima and K.
Itoh, J. Organomet. Chem., 1992, 428, C21; (h) K. U.
Baldenius, H. Tom Dieck, W. A. Koenig, D. Icheln and T.
Runge, Angew. Chem., Int. Ed., 1992, 31, 305.
2
(a) M. V. S. N. Maddipatla, M. Pattabiraman, A. Natarajan, K.
Srivastav, J. T. Mague and V. Ramamurthy, Org. Biomol.
Chem., 2012, 10, 9219; (b) A. Michaelides, S. Skoulika and
M. G. Siskos, Chem. Commun., 2011, 47, 7140.
Scheme 5
initial stages of the reaction. By carrying out the reaction at slightly
lower temperature, we were able to isolate 14a (Ar = Ph) in low
yield (9%) and confirm its structure by spectral methods. Being re-
subjected to the typical reaction conditions, 14a did not provide any
cyclic products, but slowly polymerized instead. Polymerization of
the alternate dimeric intermediate 14 under the reaction conditions
significantly simplified isolation and purification of the tricyclic
products 4, as upon completion of the reaction the crude mixture
contained only one chromatographically mobile component
accompanied by small amounts of immobile polymers.
3
4
5
6
V. A. Petrov and W. Marshall, Beilst. J. Org. Chem., 2010,
6(46), doi:10.3762/bjoc.6.46.
N. J. Turro and J. R. Williams, Tetrahedron Lett., 1969, 10
321.
T. Machiguchi, J. Okamoto, Y. Morita, T. Hagesawa, S.
Yamabe and T. Minato, J. Am. Chem. Soc., 2006, 128, 44.
(a) J. S. Yadav, K. V. R. Rao, K. Ravindar and B. V. S. Reddy,
Eur. J. Org. Chem., 2011, 58; (b) J. S. Yadav, T. S. Rao, N. N.
Yadav, K. V. R. Rao, B. V. S. Reddy and A. Al Khazim Al
Ghamdi, Synthesis, 2012, 44, 788.
H. J. Rogers, J. Chem. Soc., Perkin Trans. 1, 1995, 3073.
(a) P. Ryabchuk, A. Edwards, N. Gerasimchuk, M. Rubina and
M. Rubin, Org. Lett., 2013, 15, 6010; (b) J. E. Banning, A. R.
Prosser, B. K. Alnasleh, J. Smarker, M. Rubina and M. Rubin,
J. Org. Chem., 2011, 76, 3968; (c) J. E. Banning, A. R. Prosser
and M. Rubin, Org. Lett., 2010, 12, 1488.
,
7
8
Conclusions
In conclusion, we have demonstrated an efficient 4+4-cyclodi-
merization of (cycloprop-2-en-1-yl)methanols allowing for a single
step assembly of medium sized cyclic ethers via the simultaneous
formation of two ethereal C-O bonds. The described base-assisted,
strain release-driven transformation proceeds via a sterically-
controlled, facially-selective, intermolecular nucleophilic addition of
alkoxides across the double bond of cyclopropenes followed by a
diastereoselective ring closure, furnishing an unusual 2,7-
9
(a) J. E. Banning, J. Gentillon, P. G. Ryabchuk, A. R. Prosser, A.
Rogers, A. Edwards, A. Holtzen, I. A. Babkov, M. Rubina and
M. Rubin, J. Org. Chem., 2013, 78, 7601; (b) P. Ryabchuk, M.
Rubina, J. Xu and M. Rubin, Org. Lett., 2012, 14, 1752; (c) A.
R. Prosser, J. E. Banning, M. Rubina and M. Rubin, Org. Lett.,
2
010, 12, 3968.
1
1
0 B. K. Alnasleh, W. M. Sherrill, M. Rubina, J. Banning and M.
Rubin, J. Am. Chem. Soc., 2009, 131, 6906.
1 See Supporting Information for details.
4
,6
dioxatricyclo[7.1.0.0 ]decane core. To the best of our knowledge, 12 M. Rubina, M. Rubin and V. Gevorgyan, J. Am. Chem. Soc.,
this is the first example of a 4+4-cyclodimerization involving
nucleophilic addition of oxygen-based nucleophiles to olefin
moieties. Sterically controlled facial selectivity of the intermol-
ecular attack in the first step of the reaction translates into the high
chemoselectivity of the subsequent intramolecular cyclization.
Such “natural selection”, in which only the major intermediate, cis-
linear dimer can participate in cyclization, while the minor trans-
2004, 126, 3688.
3 A. Edwards and M. Rubin, Tetrahedron, 2015, 71, 3237.
4 X. Liu and J. M. Fox, J. Am. Chem. Soc., 2006, 128, 5600.
1
1
2
linear dimer polymerizes, results in the C -symmetric tricyclic
compounds obtained exclusively in good yields and with excellent
diastereoselectivities.
Financial support from International Collaboration Program,
supported by the Ministry of Education and Science of the Russian
Federation and the Ministry of Education of Perm Krai is gratefully
acknowledged. We also are grateful for support by the Russian
4
| J. Name., 2012, 00, 1-3
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