Preparation of highly substituted tetrahydropyrans via a metal assisted dipolar cycloaddition reaction

Article abstract of DOI:10.1039/b917332c

A range of highly substituted tetrahydropyrans have been prepared by reaction of a donor-acceptor cyclobutane, where the donor is a metal-alkyne complex, with an aldehyde under Lewis acid conditions.

Full text of DOI:10.1039/b917332c

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Preparation of highly substituted tetrahydropyrans via a metal assisted
dipolar cycloaddition reactionw
Eric A. Allart, Steven D. R. Christie,* Gareth J. Pritchard* and Mark R. J. Elsegood
Received (in Cambridge, UK) 24th August 2009, Accepted 6th October 2009
First published as an Advance Article on the web 22nd October 2009
DOI: 10.1039/b917332c
A range of highly substituted tetrahydropyrans have been
prepared by reaction of a donor–acceptor cyclobutane, where
the donor is a metal–alkyne complex, with an aldehyde under
Lewis acid conditions.
We have recently reported the use of dicobalt complexes in the
formation of new carbon–heteroatom bonds through [3+2]
cycloaddition reactions via a stabilized dipole intermediate.1
Scheme 1 Cyclobutane-dipole equilibrium.
The initial work carried out made use of substituted cyclo-
corresponding alcohol 4 using LiBH4. The diol 4 was
propanes with a metal–alkyne complex to stabilize the
Nicholas carbocation.2 The formation of a Nicholas carbocation
converted into the dibromide 5 using bromine and triphenyl-
phosphine at 0 1C (Scheme 2).
This sequence was ‘‘chromatography-free’’ and achieved in
through cleavage of a carbon–carbon s bond allowed
the synthesis of highly substituted tetrahydrofurans and
excellent yield. After complete conversion of the alcohols into
pyrrolidines in good yields.3 More recently, we have also
the corresponding bromides, the triphenylphosphine oxide
reported the use of an iron–dienyl template to facilitate a
side product was recrystallized thrice from cold petrol affording
similar reaction.4 Cycloaddition reactions involving three-
the dibromide 5 in a quantitative yield. Displacement of the
membered rings have been the subject of recent interest
two bromines with dimethyl malonate and sodium hydride
e.g. for the synthesis of tetrahydro-1,2-oxazines, pyridines,
afforded the desired cyclobutane 6 in 74% yield.
and tetrahydrofurans.5 Ghorai et al. recently reported related
The cyclobutane 6 was then complexed with dicobalt
reactions for the synthesis of substituted imidazoline starting
octacarbonyl before adding successively the aldehyde and
from aziridines and the synthesis of tetrahydropyrimidines
the Lewis acid (Scheme 3).
using azetidines.6 More recently, they also reported a SN2
Cycloaddition reactions were performed in dichloro-
type nucleophilic ring opening followed by a [4+2] cyclo-
methane at room temperature using catalytic amounts of
addition of the same azetidines with aldehydes and ketones.7
Lewis acid under an inert atmosphere.z We had expected the
However the equivalent strategy using a cyclobutane ring has
cyclobutane core would have the same reactivity as the
never been reported. We believe that the use of donor–
cyclopropane we had examined previously,1 however, the use
acceptor cyclobutanes in cycloadditions would both be a novel
of boron trifluoride as the activating Lewis acid gave only a
and useful addition to synthetic organic chemistry.
complex mixture of products. Instead we found that catalytic
We now report that a novel and efficient [4+2] cyclo-
addition reaction has been developed using cyclobutane as a
masked dipole (Scheme 1). We envisaged treating a substituted
cyclobutane 2 with a Lewis acid in order to open the four-
membered ring and reveal a stabilized dipole 1 (Scheme 2).
The malonate motif stabilizes the carbanion and the cobalt–
alkyne complex stabilizes the cation as a Nicholas cation. The
dipole could then be trapped with a suitable dipolarophile to
effect a cycloaddition reaction.
The substituted propargylic cyclobutane was prepared via a
four-step methodology in 74% overall yield. The hydroxyester
3 was prepared by simple aldol chemistry, then reduced to the
Department of Chemistry, Loughborough University, Loughborough,
Leicestershire, UK LE11 3TU. E-mail: s.d.christie@lboro.ac.uk,
g.j.pritchard@lboro.ac.uk; Fax: +44 (0)1509 223925;
Tel: +44 (0)1509 222586
w Electronic supplementary information (ESI) available: Experimental
procedures, analytical data, crystal structure diagrams for 8, 10,
and 18, and copies of NMR spectra. CCDC reference numbers
745432–745435. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b917332c
Scheme 2 Preparation of the required donor–acceptor cyclobutane.
Chem. Commun., 2009, 7339–7341 | 7339
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Scheme 3 [4+2] Cycloaddition reaction.
Table 1 Conditions and yields of cycloaddition reaction
Aldehyde (R)
Product
Time
Yield (%)
de
Fig. 1 X-Ray crystal structure of tetrahydropyran 19.
CO2Et
CH3
Ph
4-CH3Ph
2-CH3Ph
PhCHQCH
PhCHQCCH3
CH3CHQCH
CH3CHQCHCHQCH
4-CH3OPh
4-PhOPh
7
8
9
17 h
30 min
1 d
10 min
1 h
1 h
25 min
1 h
1 h
15 min
2 h
58
73
34
64
47
82
84
82
51
85
65
95
73
92
92
20%
23%
cis
cis
cis
cis
cis
cis
cis
cis
cis
cis
cis
cis
cis
10
11
12
13
14
15
16
17
18
19
20
21
2-C4H3O
2-C4H3S
2,4-(CH3O)2Ph
3,4-(CH3O)2Ph
10 min
15 min
10 min
10 min
Scheme 4 Proposed mechanism for the cycloaddition with electron
deficient aldehydes.
All diastereoselectivities were confirmed by nOe experi-
ments and, in addition, X-ray crystal structures8 were
determined for 8, 10ꢁCH2Cl2, 18 and 19 (see Fig. 1 for structure
of tetrahydropyran 19 and ESIw for those of the others).
The mechanism of the reaction is not yet known, but the
results described above suggest that two different mechanisms
are likely to occur whether the aldehyde is electron rich or
poor. If the aldehyde is electron poor the reaction is very slow
or does not proceed at all. In this case, we believe the highly
quantities of scandium triflate were the preferred additive.
A range of aldehydes were then used to trap the dipole formed
during the reaction as summarized in Table 1. No reaction was
seen without complexation of the alkyne to cobalt hexacarbonyl.
Our initial choice of trapping agent was ethyl glyoxylate, as an
electron deficient aldehyde, since electron deficient aldehydes
gave the best yields in the cyclopropane case. The two
separable diastereoisomers of the corresponding tetrahydro-
pyran adduct 7 were isolated in 58% yield with 20% de after
17 hours. Acetaldehyde also afforded its corresponding
tetrahydropyran 8 in a 73% yield with 23% de in 30 minutes,
however it was the only aliphatic aldehyde that afforded the
desired cycloadduct.
On moving to aryl aldehydes, benzaldehyde surprisingly
afforded only the cis-isomer of 9 in a moderate yield of 34%
after 24 hours. Using conjugated and aromatic aldehydes such
as cinnamaldehyde and anisaldehyde, only the cis-isomers
were produced during the reaction (12 and 16) in 82% and
85% yield, respectively, a trend that continued for other
electron rich aldehydes (e.g.18, 20 and 21). In contrast,
p-nitrobenzaldehyde gave only the complexed starting material
2, with no sign of the pyran. Thus there is a marked difference
between the three- and four-membered ring dipole precursors:
our previous studies found that electron deficient aldehydes
gave the best yields with the cyclopropane, but low diastereo-
selectivities. In contrast the cyclobutane gives significantly
better yields with electron rich aldehydes, and for the first
time, excellent stereocontrol.
To assess the effect of steric hindrance, a comparison
was made between p-tolualdehyde and o-tolualdehyde. The
p-substituted aldehyde afforded 10 in 64% yield after only
10 minutes while o-tolualdehyde gave 11 in only 47% yield
after 1 hour.
Scheme 5 Proposed mechanism for the cycloaddition with electron
rich aldehydes.
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electron deficient carbonyl is subject to attack first by the
malonate carbanion (Scheme 4).
2 For a review of the Nicholas reaction in synthesis see: B. J. Teobald,
Tetrahedron, 2002, 58, 4133.
3 For a review of donor–acceptor cyclopropanes in synthesis see:
H.-U. Reissig and R. Zimmer, Chem. Rev., 2003, 103, 1151.
4 S. D. R. Christie, J. Cummins, M. R. J. Elsegood and G. Dawson,
Synlett, 2009, 257.
5 I. S. Young and M. A. Kerr, Angew. Chem., Int. Ed., 2003, 42, 3023;
I. S. Young and M. A. Kerr, Org. Lett., 2004, 6, 139; P. D. Pohlhaus
and J. S. Johnson, J. Org. Chem., 2005, 70, 1057; T. P. Lebold,
C. A. Carson and M. A. Kerr, Synlett, 2006, 364; Y.-B. Kang,
Y. Tang and X.-L. Sun, Org. Biomol. Chem., 2006, 4, 299.
6 M. K. Ghorai, K. Das, A. Kumar and A. Das, Tetrahedron Lett.,
2006, 47, 5393; M. K. Ghorai, K. Ghosh and K. Das, Tetrahedron
Lett., 2006, 47, 5399.
When electron rich or conjugated aldehydes are used, the
oxygen of the carbonyl will attack the Nicholas carbocation
first, through delocalization of p electrons. In this case the
mechanism is not concerted, the carbon–oxygen bond can
rotate to obtain the most stable conformation before trapping
the carbanion which may explain why only the cis-isomer is
obtained (Scheme 5).
In summary, we have synthesized an alkynyl cyclobutane in
74% yield over 4 steps. We report for the first time a formal
[4+2] cycloaddition reaction using a cyclobutane as a dipole
7 M. K. Ghorai, K. Das and A. Kumar, Tetrahedron Lett., 2007, 48,
4373.
precursor, providing
a new way for the synthesis of
8 Crystal data for 8: C24H20Co2O11, M = 602.26, monoclinic, C2/c,
a = 30.4100(16), b = 8.0633(4), c = 22.1301(12) A, b =
six-membered heterocycles in a diastereoselective fashion. A
wide range of aldehydes was used as trapping reagents to form
tetrahydropyrans in good yields (up to 95%) and with
excellent diastereoselectivities in some cases. Further work
is under way to expand the scope of this reaction. The
importance of the area has been underlined by the recent
report of a related carbocyclic version [4+2] cycloaddition.9
109.3822(8)1,
U = T = 150(2) K, Z = 8,
5118.9(5) A3,
m(Mo-Ka) = 1.354 mmꢂ1, 25 700 reflections measured, 6367 unique
(Rint = 0.0430) which were used in all calculations, wR2 = 0.0877
for all data, R1 = 0.0360 for 4643 data with F2 Z 2s(F2). Crystal
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data for 10ꢁCH2Cl2: C31H26Cl2Co2O11, M = 763.28, triclinic, P1,
a = 9.2516(12), b = 13.8248(19), c = 14.0220(19) A, a =
109.6525(19)1,
b = 91.9541(19)1, g = 104.8855(19)1, U =
1617.9(4) A3, T = 150(2) K, Z = 2, m(Mo-Ka) = 1.249 mmꢂ1
,
12 711 reflections measured, 5678 unique (Rint = 0.0322) which were
used in all calculations, wR2 = 0.2425 for all data, R1 = 0.0774 for
4097 data with F2 Z 2s(F2). Modeled with two-fold disorder in one
CO2Me group and the solvent of crystallization. Crystal data for 18:
Notes and references
z Typical procedure for cycloaddition reactions: substituted cyclo-
butane 2 (70 mg) was dissolved in DCM (0.5 M) in a 10 mL oven
dried round-bottom flask and activated molecular sieves were added
(150 mg). Dicobalt octacarbonyl (1.1 equiv.) was added and the
reaction mixture was allowed to stir at room temperature under
nitrogen atmosphere for 1.5 hour. Aldehyde (3 equiv.) was added
followed by scandium triflate (5 mol%) and the resulting mixture was
allowed to stir at room temperature. (Refer to Table 1 for reaction
times.) When the reaction was completed (TLC monitoring), the crude
mixture was filtered through a pad of celite and silica and the solvent
was evaporated in vacuo. The product was purified by flash chromato-
graphy on silica gel (5% ethyl acetate–petrol).
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C27H20Co2O12, M = 654.29, triclinic, P1, a = 8.0886(5), b =
11.7239(7), c = 15.7788(9) A, a = 106.5335(8)1, b = 102.7961(9)1,
g = 91.9661(9)1, U = 1391.20(14) A3, T = 150(2) K, Z = 2,
m(Mo-Ka) = 1.255 mmꢂ1, 16 756 reflections measured, 8572 unique
(Rint = 0.0176) which were used in all calculations, wR2 = 0.0807
for all data, R1 = 0.0313 for 6949 data with F2 Z 2s(F2). Crystal
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data for 19: C27H20Co2O11S, M = 670.35, triclinic, P1, a =
8.6480(5), b = 12.0683(7), c = 14.2184(9) A, a = 107.2871(9)1,
b = 93.7267(9)1, g = 91.7003(9)1, U = 1412.03(15) A3, T = 150(2) K,
Z = 2, m(Mo-Ka) = 1.308 mmꢂ1, 17 036 reflections measured, 8495
unique (Rint = 0.0202) which were used in all calculations,
wR2 = 0.0844 for all data, R1 = 0.0323 for 7011 data with F2 Z 2s(F2).
9 Added in press: J. Matsuo, S. Sasaki, T. Hoshikawa and
H. Iahibashi, Org. Lett., 2009, 11, 3822; J. Matsuo, S. Negishi
and H. Ishibashi, Tetrahedron Lett., 2009, 50, 5831.
1 S. D. R. Christie, R. J. Davoile, M. R. J. Elsegood, R. Fryatt,
R. C. F. Jones and G. J. Pritchard, Chem. Commun., 2004, 2474;
S. D. R. Christie, R. Davoile and R. C. F. Jones, Org. Biomol.
Chem., 2006, 4, 2683.
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Chem. Commun., 2009, 7339–7341 | 7341