Medium-sized rings versus macrocycles through rhodium-catalyzed ring-expansion reactions of cyclic acetals

Article abstract of DOI:10.1002/chem.201103870

α-Diazo β-ketoesters and diketones react with cyclic acetals under Rh^II catalysis to yield unprecedented polyoxygenated 8- and 9-membered rings in one pot. The reactions occur under mild conditions with yields up to 90 %. A perfect regioselectivity is obtained, which can be rationalized through a mechanistic hypothesis that considers 1) the formation of an oxonium ylide, 2) its transformation into an unsaturated acyclic oxocarbenium electrophilic intermediate, and 3) an intramolecular nucleophilic attack in a direct application of Baldwin's rules. Copyright

Full text of DOI:10.1002/chem.201103870

FULL PAPER
DOI: 10.1002/chem.201103870
Medium-Sized Rings versus Macrocycles through Rhodium-Catalyzed Ring-
Expansion Reactions of Cyclic Acetals
Rafael Ballesteros-Garrido,[a] Diane Rix,[a] Cꢀline Besnard,[b] and Jꢀrꢁme Lacour*[a]
Abstract: a-Diazo b-ketoesters and diketones react with cyclic acetals under RhII
catalysis to yield unprecedented polyoxygenated 8- and 9-membered rings in one
pot. The reactions occur under mild conditions with yields up to 90%. A perfect
regioselectivity is obtained, which can be rationalized through a mechanistic hy-
pothesis that considers 1) the formation of an oxonium ylide, 2) its transformation
into an unsaturated acyclic oxocarbenium electrophilic intermediate, and 3) an in-
tramolecular nucleophilic attack in a direct application of Baldwinꢀs rules.
Keywords: carbenoids · diazo com-
pounds · medium-ring compounds ·
rhodium · ylides
Introduction
Oxonium ylides, which can be prepared by the reactions of
singlet carbenes and metal carbenoids with ether molecules,
are valuable reactive intermediates.[1] They undergo a variety
of synthetic transformations including [1,2]- and [2,3]-Ste-
vens rearrangements.[1d,g,2] Products of higher molecular
complexity can often be obtained through a series of intra-
and intermolecular reactions.[3] For instance, oxonium ylides
and small cyclic ethers (with a ring size of six or less) react
together and yield polyoxygenated 15- to 22-membered
macrocycles in a single pot.[4] In this context, our group has
recently shown that dirhodium-catalyzed decompositions of
a-diazocarbonyls 1 in the presence of oxetanes affords 15-
membered rings of type 2 [Eq. (1)].[4e] Under virtually the
same conditions, 16- or 18-membered rings 3 and 4 are ob-
tained when THF, tetrahydropyran (THP), or 1,4-dioxane
are used as solvents instead [Eqs. (2) and (3)].[4d] These re-
sults were rationalized by considering the formation of oxo-
nium ylide intermediates 5–7 and their subsequent dimeriza-
tion or successive intermolecular reactions with ether
molecules.
Of importance to the current study, macrocycles 2–4 were
formed as the major products of these reactions. Simpler 7-,
8-, or 9-membered rings of type 8, 9, and 10 [Eqs. (4), (5)
and (6)], which could have resulted from intramolecular re-
actions of nucleophilic and electrophilic sites within ylides 5,
6, and 7, were either not observed or appeared only in trace
[a] Dr. R. Ballesteros-Garrido, Dr. D. Rix, Prof. J. Lacour
Dꢁpartement de Chimie Organique
Universitꢁ de Genꢂve
quai Ernest Ansermet 30
1211 Geneva 4 (Switzerland)
Fax : (+41)22-379-3215
E-mail: jerome.lacour@unige.ch
[b] Dr. C. Besnard
Laboratoire de Cristallographie
Universitꢁ de Genꢂve
quai Ernest Ansermet 24
1211 Geneva 4 (Switzerland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103870.
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amounts.[4a,5] Herein, in a mechanistic exercise with synthetic
applications, the macrocyclic reactivity is directed towards
the exclusive formation of analogues of 8, 9, and 10; this
was achieved through the direct application of Baldwinꢀs
rules[6] and a modification of the oxo-nucleophiles. In fact,
the simple use of cyclic acetals instead of ethers allows the
preparation of unprecedented medium-sized 8- or 9-mem-
bered rings.[7]
of the availability of 1,3-dioxolane, 1,3-dioxane, and 1,3,5-
trioxane, it was easy to test the concept using these mole-
cules as solvent or reactant.
We first focused on the reactivity of 1,3-dioxane 13
[Eq. (7)] with a-diazo ketoesters 1a–i and diketones
1j–l (Scheme 2); the results are summarized in Table 1. The
reactions were performed under conditions similar to those
Results and Discussion
Intermediates 5–7 form either predominantly or exclusively
15-, 16- and 18-membered rings of type 2–4.[4d,e] The reason
for this macrocyclic preference was investigated. The re-
quirement for nucleophilic additions on the oxonium part of
the ylide intermediates to proceed through SN2-like transi-
tion states (i.e., with 1808 bond angles between entering and
internal leaving groups) was proposed to explain this reac-
tivity.[8] In other words, in compliance with Baldwinꢀs rules
5, 6, and 7 cannot undergo intramolecular 5-endo-tet cycliza-
tion reactions due to their constrained geometry;[6] the accu-
mulation of the observed products 2–4, arises from subse-
quent dimerization of the intermediates 5–7 or successive in-
termolecular reactions with ether solvent molecules.
To verify the analysis, we wanted develop a way to bypass
the usual reactivity and enforce the synthesis of medium-
sized rings. Ideally, this change of reactive pathway would
be made possible by a simple modification of the skeleton
of one of the two reactive partners — and the cyclic ether
moiety in particular. In fact, a change to the sp3 nature of
the electrophilic center next to the ether oxygen was re-
quired; its tetrahedral geometry tends to enforce SN2-like
transition states and disfavor n-endo-tet cyclization reactions
(nꢀ8).[8] As a possible solution, its replacement by a trigonal
sp2 center was considered because, in this case, n-endo-trig
cyclization reactions would then be allowed.
Under this working hypothesis, ways to “transform” a tet-
rahedral sp3 into a trigonal sp2 center were looked for. The
easiest solution seemed to be the introduction of a second
oxygen atom in a 1,3-relationship to the first. Upon reaction
with the carbenoid, the cyclic acetal would form an oxonium
ylide intermediate (11; Scheme 1) that would then collapse
into an acyclic derivative 12 through a ring-opening induced
by a lone-pair of the second oxygen atom. The resulting in-
termediate 12 is an oxocarbenium moiety that is ideally
suited to undergo n-endo-trig cyclization reactions.[9] In view
Scheme 2. Diazo compounds 1 selected for the study.
already reported with 1,4-dioxane.[4d] For instance, ethyl di-
azoacetoacetate 1a was added at 608C to a solution of
ACHUTNGREN[NUG Rh2CAHTUNGTNER(NUGN OAc)4] (1.0 mol%). The reaction was over in less than
2 h. NMR spectroscopic analysis of the crude reaction mix-
ture indicated the formation of a single product 14a; a new
cyclic derivative was isolated in 72% yield (Table 1,
entry 1). To our satisfaction, through mass spectrometry
(ESI: m/z 216.1 [M+H+]), IR (1628 cmÀ1), and detailed
NMR (HMBC, HSQC) analyses, an enediol acetal structure
of type 14 was ascertained; the connectivity and 9-mem-
bered ring structure of which was confirmed by X-ray dif-
fraction analysis (see Figure 1 below). The origin of the per-
fect regioselectivity will be discussed later.[10] In terms of
synthesis, [Rh2ACHTNUTRGENN(UG Oct)4] and [Rh2ACHTUGNTREN(NUNG OAc)4] behaved similarly;
however, the latter, being less expensive, was preferred for
further studies. Performing the reaction at 0.5 and 1.0m con-
centrations of 1a gave the same results. However, because
[Rh2ACHTNUTRGNEU(GN OAc)4] is only partially soluble at a concentration of
1.0m, further reactions were performed using 0.5m of diazo
reagent.
Variations on the ester side chains were investigated
(R1 =OMe, OCH2(3,5-F2C6H3), OtBu), resulting in the for-
mation of analogous derivatives 14b, 14c, and 14d. Al-
though spectroscopic evidence indicated that these com-
Scheme 1. Modification of the reactive pathway towards the exclusive
formation of medium-sized rings.
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Synthesis of Medium-Sized Rings
FULL PAPER
Table 1. Substrate scope with 1,3-dioxane 13, 1,3-dioxolane 18 and 1,3,5-trioxane 21.
amples show that the “intermo-
lecular” cyclization procedure
competes favorably with well-
established
reactions.
intramolecular
Phenyl and n-propyl substitu-
ents were then introduced a to
the carbonyl group of the diazo
reagent (Table 1, entries 7 and
8). The expected products 14g
and 14h were, however, ob-
tained in only 19 and 13%
yield, respectively. In this series,
steric hindrance impedes the re-
action to a greater extent.[14]
Coumarine derivative 1i was
then tested. Usually, in this
type of reaction, this substrate
behaves differently from other
a-diazo ketoesters.[4b] However,
no such difference was ob-
served in this case, and the cor-
responding 9-membered ring
compound 14i was obtained as
a single product (46% yield;
Table 1, entry 9). This deriva-
tive was found to be moderate-
Diazo
R1
R2
Product[a]
Yield
[%][b]
Product[a]
Yield
[%][b]
Product[a]
Yield
[%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
OEt
Me
Me
Me
Me
Me
Me
Pr
14a
14b
14c
14d
14e
14 f
14g
14h
72
40
41
37
30
14
19
13
19a
19b
19c
19d
19e
19 f
19g
19h
90
46
65
39
57
56
58
15
20a
20b
20c
20d
20e
20 f
20g
20h
53
85
59
31
32
49
34
0
OMe
OCH
OtBu
OCH2CH=CHPh
OCH2CH2Ph
OEt
2ACHTUNGTRENNUNG(3,5-F2Ph)
OEt
Ph
9
1i
14i
46
19i
67
20i
59
10
11
12
1j
1k
1l
Me
Me
14j
40
67
77
19j
19k
19l
46
68
77
20j
20k
20l
44
58
75
-CH2CH2CH2-
-CH2CACHTUNGTRENNUNG(CH3)2CH2-
14k[d]
14l[d]
[a] Reagents and conditions (Procedure A): 1a–i (1 equiv), 0.5m in 13 or 15 as solvent, [Rh
2 h, 608C. [b] Isolated product yield after filtration over neutral alumina. [c] Reagents and conditions (Proce-
dure B): 1a–i (1 equiv), 17 (20 equiv), [Rh2A(OAc)4] (1 mol%), toluene (0.2m), 2 h, 608C. [d] 258C, 12 h.
2ACHTUNGTREN(NUNG OAc)4] (1 mol%),
CTHUNGTRENNUNG
pounds were formed as the sole products of the reactions,
they were, however, isolated in only moderate yields (40, 41,
and 37% respectively; Table 1, entries 2–4). The low isolat-
ed yields were attributed to an acute volatility and a sensitiv-
ity to the chromatographic purification conditions.
Further variations were performed with allylic and homo-
benzylic derivatives 1e and 1 f. These reactants are known
to undergo intramolecular cyclopropanation[11] and CH in-
sertion[12] reactions under dirhodium catalysis; reactions that
should compete with the process under investigation. When
the crude mixtures were examined, product 14e (30%) was
found to be present along with the bicyclic [3.1.0] lactone 15
[8.3:1.0 ratio, Eq. (8)].[13] With 1 f, medium-sized ring com-
pound 14 f (14%) was also found to predominate [2.0:1.0
ratio with the monocyclic lactone 16, Eq. (9)]. These two ex-
ly soluble in heptane and a slow diffusion of this solvent
into a solution of 14i in dichloromethane afforded X-ray
quality crystals. A structural analysis was performed that un-
ambiguously confirmed the 9-membered ring structure and
also the regioselectivity of the reaction (Figure 1); the acetal
group indeed being linked to the oxygen atom belonging to
the former carbonyl group.
Figure 1. ORTEP view of the crystal structure of 14i. Thermal ellipsoids
are drawn at 50% probability.
Finally, the reaction was performed with more reactive di-
azodiketones 1j–l (Table 1, entries 10–12). The correspond-
ing products were obtained in moderate to good yields (14j,
14k, and 14l in 40, 67, and 77% yields, respectively). With
reactants 1k and 1l, it was necessary to decrease the reac-
tion temperature to 258C because side products 17k and 17l
were observed at 608C. According to NMR analyses, these
À
products arise from C H insertion reactions (Scheme 3),
which, interestingly, present a regioselectivity different to
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J. Lacour et al.
solutions of 1,3,5-trioxane 21 (20 equiv) in toluene as solvent
[Eq. (11)]. In essentially all cases,[16] the corresponding 9-
membered rings were isolated (31–85%; Table 1). As for
compounds 14 and 19, lower yields were usually caused by
volatility and a sensitivity of the products towards the purifi-
cation conditions because crude reaction mixtures contained
essentially a single adduct.[17] Furthermore, as for the previ-
ous two series, X-ray quality crystals were obtained from
the coumarin-derived adduct and a structural analysis of 20i
was performed. The result, which is shown in Figure 3, clear-
Scheme 3. Competition between 9-membered ring 14k–l formation and
À
C H insertion reactions.
that usually observed.[15] Unfortunately, these adducts de-
composed upon purification.
Having established this set of results by employing 1,3-di-
oxane 13, we turned our attention to the use of 1,3-dioxo-
lane 18 as reactant, expecting little differences in reactivity
[Eq. (10)]. In fact, rather similar results were obtained using
the previously developed conditions (diazo (0.5m),
ACHTUNGTRENNUNG[Rh2ACHTUNGTRENNUNG(OAc)4] (1.0 mol%), 608C, 2 h). In all cases, trioxo 8-
membered rings of type 19 were isolated from the reactions
of diazo compounds 1a–l. As for the previous series, compo-
sition and regiochemistry were established by spectrometric,
spectroscopic, and X-ray diffraction analyses. The solid state
structure of 19i is depicted in Figure 2.
Figure 3. ORTEP view of the crystal structure of 20i. Thermal ellipsoids
are drawn at 50% probability.
ly shows the unique 9-membered ring structure with the
three acetal moieties in a row.
These results indicate that the initial mechanistic hypothe-
sis is correct. Most likely, the reaction pathway involves the
generation of an electrophilic metal carbenoid of type 22
(Scheme 4). Nucleophilic attack of an oxygen atom from the
cyclic acetal generates the corresponding oxonium ylide of
type 11. In the three cases studied, the lone-pair of the un-
bound oxygen atom provokes an opening of the acetal ring
leading to the formation of unsaturated oxocarbenium ions
Figure 2. ORTEP view of the crystal structure of 19i. Thermal ellipsoids
are drawn at 50% probability.
Globally, the reactions performed equally well or better
with 1,3-dioxolane, with those involving diazo compounds
1a, 1d, 1e, 1 f, and 1i, in particular (see Table 1); in these
cases, isolated product yields were improved by at least
18%. Products 19e and 19 f were isolated in 57 and 56%
yields, respectively (instead of 30 and 14% for 14e and
14 f). The reason for these improved yields was due to the
absence of competing cyclopropanation or CH insertion re-
actions. Finally, diazo compounds 1j–l were reacted in 1,3-
dioxolane and the corresponding products were obtained in
moderate to good yields (19j, 19k, and 19l yields 46, 68,
and 77%; Table 1, entries 10–12). Interestingly, no side
products were detected even at 608C.
Following these precedents, compounds of type 20 bearing
four (instead of three) oxygen atoms in the medium-sized
ring were also prepared. Reactions were performed using
Scheme 4. Mechanistic proposal.
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Synthesis of Medium-Sized Rings
FULL PAPER
of type 12.[18] As discussed previously, this trigonal sp2
center is now amenable to intramolecular nucleophilic
attack, in this case from the carbonyl oxygen atom, leading
to the medium-sized cyclic products. In addition, this ration-
ale fully explains the regiochemistry observed in the reac-
tions and the perfect selectivity.
Finally, to further examine the details of the reaction, re-
actions were performed with unsymmetrical 4-methyl-1,3-di-
oxane 23 and 4-methyl-1,3-dioxolane 24; the presence of the
extra methyl group leading to possible regioisomeric adducts
(Scheme 5). Interestingly, in the case of 23, a single regioiso-
Experimental Section
General Procedure A with 1,3-dioxolane (13) and 1,3-dioxane (18): In
a 1 mL screw-cap vial equipped with a magnetic stirring bar, [Rh2A(OAc)4]
CHTUNGTRENNUNG
(5.0 mm solution in 1,3-dioxane or dioxolane (flushed with argon),
0.640 mL) was added in one portion to the diazo compound (0.32 mmol).
The reaction vial was then flushed with argon and capped. The reaction
was stirred at 608C and monitored by thin-layer chromatography (TLC,
neutral alumina). Upon completion, the reaction mixture was analyzed
and then purified on a short chromatography column (neutral Al2O3).
General Procedure B with 1,3,5-trioxane 21: In a 3 mL screw-cap vial
equipped with a magnetic stirring bar, a solution of trioxane (6.4 mmol)
and [Rh2ACTHNUGTRNE(UNG OAc)4] (0.0032 mmol) in toluene (1.750 mL; flushed with
argon) was added in one portion to the diazo compound (0.32 mmol).
The vial was flushed with argon and capped. The reaction was stirred at
608C and monitored by TLC (neutral alumina). Upon completion, triox-
ane was removed under reduced pressure and the reaction mixture was
then analyzed and purified on a short chromatography column (neutral
Al2O3).
CCDC-857512 (14i), CCDC-857513 (19i), and CCDC-857514 (20i) con-
tain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Scheme 5. Reactions in the presence of 4-methyl-1,3-dioxane (23) and
4-methyl-1,3-dioxolane (24).
Acknowledgements
We thank the University of Geneva and the Swiss NSF for financial sup-
port. We also acknowledge the contributions of the Sciences Mass Spec-
trometry (SMS) platform at the Faculty of Sciences, University of
Geneva.
mer 25 was formed during the reaction; the structure of
which was assigned by NMR spectroscopic analysis. A simi-
lar result was obtained for the reaction with 24, although
a minor isomer could be detected in the crude reaction mix-
ture (92:8 regioisomeric ratio). Clearly, and not surprisingly,
these results indicate that the less-hindered oxygen atom
(without the adjacent alkyl substituent) reacts first with the
electrophilic metallocarbene. The second oxygen atom, next
to the methyl group, then helps generate the electrophilic
oxocarbenium intermediate that is trapped to form the
products with the observed regioselectivity. These results
demonstrate that steric hindrance plays a role in the initial
oxonium ylide formation.[19]
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Conclusion
An original strategy for the one-pot synthesis of polyoxy-
genated 8- and 9-membered rings has been presented. The
approach features an unusual [Rh2ACHTUNRTGNEUNG(OAc)4]-catalyzed reactiv-
ity of a-diazo b-ketoesters and diketones with cyclic acetals.
The reactions occur under mild conditions with yields up to
90% to form unprecedented medium-sized rings. A perfect
regioselectivity was obtained due to the formation of oxoni-
um-ylide intermediates and their selective transformation
into unsaturated acyclic oxocarbenium electrophiles. Intra-
molecular nucleophilic attacks can then occur readily to
afford the eight- and nine-membered rings in a direct appli-
cation of Baldwinꢀs rules. Further applications of this ap-
proach are underway.
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Received: December 9, 2011
[9] n-Endo-trig cyclizations are favored when nꢁ6.
Published online: && &&, 2012
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6
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www.chemeurj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of Medium-Sized Rings
FULL PAPER
Medium-Ring Compounds
R. Ballesteros-Garrido, D. Rix,
C. Besnard, J. Lacour* ...... &&&& — &&&&
Medium rings: a-Diazo b-ketoesters
and diketones react with cyclic acetals
under RhII catalysis to yield unprece-
dented polyoxygenated 8- and 9-mem-
bered rings in one pot (see scheme).
The reactions occur under mild condi-
tions with yields up to 90%. The
medium-sized ring formation and per-
fect regioselectivity are direct conse-
quences of Baldwinꢀs rules.
Medium-Sized Rings versus Macrocy-
cles through Rhodium-Catalyzed Ring-
Expansion Reactions of Cyclic Acetals
Chem. Eur. J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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ÞÞ
These are not the final page numbers!