Reactivity of 13,13-dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane toward organolithiums: Remarkable resistance to the DMS rearrangement

Article abstract of DOI:10.1021/jo800054p

(Chemical Equation Presented) Reactions of dibromocyclopropane 2a, containing two spiro-fused 1,3-dioxane rings, with MeLi gave only the methylation products 8 and 9 even at elevated temperatures. In contrast, the cyclohexane analogue 2b treated with MeLi underwent a smooth rearrangement to bicyclo[1.1.0]butane 11b at -78, -10, or +35 °C. Treatment of 2a with PhLi gave the α-Ph anion 13 as the only product, which underwent smooth methylation with MeI to give 14. Under the same conditions, 2b with PhLi gave bicyclo[1.1.0]butane 11b accompanied by bromophenyl derivative 8b. Treatment of either dibromide with f-BuLi gave a mixture of products including debrominated cyclopropanes 12. Experimental results were augmented with DFT calculations for salts 23 and MP2//DFT-level calculations for carbenes 22. They demonstrated a higher stability of the dioxane α-bromo anion with respect to α-elimination by 4.8 kcal/mol and also a lower tendency of the carbene 22a to undergo rearrangement by 4.0 kcal/mol than the cyclohexane analogues. These differences have been attributed to the inductive effect of the four oxygen atoms, which results in lower LUMO energy, the higher positive charge at the carbenic center, and the overall more electrophilic character of carbene 22a as compared to the cyclohexane derivative 22b. The rearrangement of carbenes 22 to the corresponding allenes 1, the thermodynamic products, requires a higher activation energy ΔG^?₂₉₈ by 4.2 kcal/mol for dioxane and 6.4 kcal/mol for cyclohexane derivatives than for the formation of the bicyclo[1.1.0]butanes 11. The ΔG^?;₂₉₈ for intramolecular insertions to the C-H bond is low and calculated as 6.0 kcal/mol for dioxane 22a and 2.0 kcal/mol for the formation of cyclohexane 22b.

Full text of DOI:10.1021/jo800054p

Reactivity of
13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane toward
Organolithiums: Remarkable Resistance to the DMS
Rearrangement†
Wendy Eccles, Marcin Jasinski,‡ Piotr Kaszynski,* Katarzyna Zienkiewicz, Baldur Stulgies,
and Aleksandra Jankowiak
Organic Materials Research Group, Department of Chemistry, Vanderbilt UniVersity,
NashVille, Tennessee 37235
piotr.kaszynski@Vanderbilt.edu
ReceiVed January 9, 2008
Reactions of dibromocyclopropane 2a, containing two spiro-fused 1,3-dioxane rings, with MeLi gave
only the methylation products 8 and 9 even at elevated temperatures. In contrast, the cyclohexane analogue
2b treated with MeLi underwent a smooth rearrangement to bicyclo[1.1.0]butane 11b at -78, -10, or
+35 °C. Treatment of 2a with PhLi gave the R-Ph anion 13 as the only product, which underwent smooth
methylation with MeI to give 14. Under the same conditions, 2b with PhLi gave bicyclo[1.1.0]butane
11b accompanied by bromophenyl derivative 8b. Treatment of either dibromide with t-BuLi gave a mixture
of products including debrominated cyclopropanes 12. Experimental results were augmented with DFT
calculations for salts 23 and MP2//DFT-level calculations for carbenes 22. They demonstrated a higher
stability of the dioxane R-bromo anion with respect to R-elimination by 4.8 kcal/mol and also a lower
tendency of the carbene 22a to undergo rearrangement by 4.0 kcal/mol than the cyclohexane analogues.
These differences have been attributed to the inductive effect of the four oxygen atoms, which results in
lower LUMO energy, the higher positive charge at the carbenic center, and the overall more electrophilic
character of carbene 22a as compared to the cyclohexane derivative 22b. The rearrangement of carbenes
22 to the corresponding allenes 1, the thermodynamic products, requires a higher activation energy ∆Gq
298
by 4.2 kcal/mol for dioxane and 6.4 kcal/mol for cyclohexane derivatives than for the formation of the
bicyclo[1.1.0]butanes 11. The ∆Gq298 for intramolecular insertions to the CsH bond is low and calculated
as 6.0 kcal/mol for dioxane 22a and 2.0 kcal/mol for the formation of cyclohexane 22b.
Introduction
The Doering-Moore-Skattebøl (DMS) method1–3 represents
a general and convenient route to substituted allenes I (Figure
1).4,5 The reaction involves a rearrangement of cyclopropylidene
II, which typically is generated from the corresponding dibro-
mocyclopropane III by lithium-halogen exchange followed by
R-elimination of the bromide ion from IV.6 The rearrangement
of the parent carbene has been the subject of detailed experi-
FIGURE 1. General reaction pathways for transformation of gem-
† Described in part in W. Eccles M.Sci. Thesis, Vanderbilt University, 2005.
* To whom correspondence should be addressed. Phone: (615) 322-3458.
‡ A visiting student from the laboratory of Professor Grzegorz Mloston´,
University of Ło´dz´, Ło´dz´, Poland.
(1) Doering, W. v. E.; LaFlamme, P. M Tetrahedron 1958, 2, 75–79.
(2) Moore, W. R.; Ward, H. R. J. Org. Chem. 1960, 25, 2073.
(3) Skattebøl, L. Tetrahedron Lett. 1961, 5, 167–172.
dibromocyclopropanes.
mental and theoretical investigations,7–9 which conclude that
the reaction is generally characterized by a low activation
energy. The formation of allenes I from dibromocyclopropanes
III often competes with the formation of bicyclo[1.1.0]butanes
5732 J. Org. Chem. 2008, 73, 5732–5744
10.1021/jo800054p CCC: $40.75 2008 American Chemical Society
Published on Web 06/26/2008

ReactiVity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane
SCHEME 1
SCHEME 2
(BCB) V, which are formed in quantities ranging from traces
to exclusive products.10–14 This competition between the two
pathways for rearrangement of II is governed by the substituents,
which exert steric strain,8,15 conformational change,16 or rarely
electronic effects.13,15,17
The formation of carbene II (or a carbenoid) by R-elimination
from the initial R-bromo anion IV is generally fast at temper-
atures above -50 °C,18 which are typical conditions for the
DMS rearrangement.3 In rare cases, the R-elimination step is
slow and the anion is alkylated by an alkyl halide generated in
a lithium-halogen exchange reaction to form VI in quantities
ranging from 2 to 13%.19–22 An electron-withdrawing hetero-
atom is usually present in these cases, and the alkylation has
been attributed to the stability of the bromolithium intermediate
IV resulting from intramolecular coordination with oxygen21,23,24
or sulfur.20 In other cases, an alkyl halide was added to the
reaction mixture at temperatures <-70 °C to avoid the DMS
rearrangement and to obtain the desired alkylation product.25,26
In the course of our work on functionalized spirocyclic
systems, we focused on protected tertakis(hydroxymethyl)allene
1a and envisioned its formation by the DMS rearrangement of
the corresponding dibromocyclopropane 2a (Scheme 1). This
expectation was based on the reported efficient rearrangements
of the cyclopropyl27 and cyclobutyl28 analogues of 2a to the
corresponding allenes. Surprisingly, the precursor 2a demon-
strated a significant resistance to the rearrangement, and neither
desired allene 1a nor other products of rearrangement could be
detected directly. For a better understanding of this result, we
also investigated a similar reaction with the cyclohexane
analogue 2b.
Here, we report the preparation of cyclopropanes 2a and 2b
and their reactions with MeLi, PhLi, and t-BuLi. The experi-
mental data presented in the Results were augmented with
computational analysis and constitute the basis for mechanistic
considerations presented in the Discussion.
Results
(4) For leading references, see: (a) Sydnes, L. K. Chem. ReV. 2003, 103,
1133–1150. (b) Landor, S. R. In The Chemistry of the Allenes; Landor, S. R.,
Ed.; Academic Press: New York, 1982; Vol. 1. (c) Schuster, H. F.; Coppola,
G. M. Allenes in Organic Synthesis; Wiley & Sons: New York, 1984; Chapter
2, pp 20-26.
(5) For recent references, see: (a) Lee-Ruff, E. In Carbocyclic Three- and
Four-membered ring compounds; de Meijere, A., Ed.; Methoden der Organischen
Chemie, Vol. E17c; Thieme-Verlag: New York, 1997; pp 2388-2418. (b)
Backes, J; Brinker, U. H. In Carbene (carbenoide); Regitz, M., Ed.; Methoden
der Organischen Chemie, Vol. E19b; Thieme-Verlag: New York, 1989; pp 391-
491.
Synthesis of Dibromocyclopropanes 2. The synthesis of
dibromide 2 was accomplished by dibromocarbene addition to
the corresponding alkene 3 (Scheme 2). Cyclopropanation of
5,5′-bi[1,3-dioxanylidene] (3a) under PTC conditions29 over-
night resulted in a mixture of starting material and dibromide
1
2a in a 2:3 ratio (determined by H NMR), and the product
was isolated in 19% yield. A prolonged reaction time did not
change the ratio. However, nearly complete conversion of 3a
was achieved after several additions of more base and catalyst,
and the product was isolated in about 35% yield after 3 days of
stirring. In contrast, the cyclopropanation reaction of olefin 3b
under identical conditions went to completion overnight, and
dibromide 2b was obtained in 55% yield. In an attempt to
improve the yield of 2a, PhHgCBr3 was used as the source of
dibromocarbene recommended for weakly nucleophilic olefins.30
Thus, a reaction of 3a with 1.5 equiv of PhHgCBr3 proceeded
to about 50% conversion, and cyclopropane 2a was isolated in
28% yield.
The preparation of olefin 3a was reported in the literature as
a component of a mixture or a sole product of a reaction between
5-bromo-5-nitro[1,3]dioxane (4) and EtSNa31 or the lithium salt
of 5-nitro[1,3]dioxane32 (5) in DMSO (Scheme 3). The reported
80% yield of 3a could not be reproduced despite our efforts.
Numerous reactions closely following the literature procedure31
and using either carefully dried reagents under strictly anaerobic
atmosphere or just reagent grade DMSO gave the same and
(6) For selected references, see: (a) Boche, G.; Walborsky, H. M. In
Cyclopropane deriVed reactiVe intermediates; Patai, S., Rappoport, Z., Eds.;
Wiley & Sons: New York, 1990; Chapter 4. (b) Braun, M. In The chemistry of
organolithium compounds; Rappoport Z., Marek, I., Eds.; Wiley & Sons: India,
2004; pp 829-900.
(7) Valtazanos, P.; Elbert, S. T.; Ruedenberg, K. J. Am. Chem. Soc. 1986,
108, 3147–3149.
(8) Bettinger, H. F.; Schleyer, P. v., R.; Schreiner, P. R.; Schaefer, H. F. J.
Org. Chem. 1997, 62, 9267–9275.
(9) Bettinger, H. F.; Schreiner, P. R.; Schleyer, P. v., R.; Schaefer, H. F. J.
Phys. Chem. 1996, 100, 16147–16154.
(10) Skattebøl, L. Tetrahedron Lett. 1970, 2361–2364.
(11) Moore, W. R.; Taylor, K. G.; Mu¨ller, P.; Hall, S. S.; Gaibel, Z. L. F.
Tetrahedron Lett. 1970, 2365–2368.
(12) Sydnes, L. K.; Skattebøl, L. Acta Chem. Scand. B 1978, 32, 547–552.
(13) Creary, X.; Jiang, Z.; Butchko, M.; McLean, K. Tetrahedron Lett. 1996,
37, 579–582.
(14) Moore, W. R.; Hill, J. B. Tetrahedron Lett. 1970, 4343–4346, and 4553-
4556.
(15) Baird, M. S. J. Chem. Soc., Chem. Commun. 1979, 776–777.
(16) (a) Taylor, K. G.; Chaney, J. J. Am. Chem. Soc. 1976, 98, 4158–4163.
(b) Taylor, K. G.; Chaney, J.; Deck, J. C. J. Am. Chem. Soc. 1976, 98, 4163–
4167.
(17) Baird, M. S. J. Chem. Soc., Chem. Commun. 1971, 1145–1146.
(18) (a) Seebach, D.; Ha¨ssig, R.; Gabriel, J. HelV. Chim. Acta 1983, 66, 308–
337. (b) Seebach, D.; Siegel, H.; Mu¨llen, K.; Hiltbrunner, K. Angew. Chem.,
Int. Ed. 1979, 18, 784–185.
(19) Marquis, E. T.; Gardner, P. D. Tetrahedron Lett. 1966, 2793–2798.
(20) Arct, J.; Skattebøl, L. Acta Chem. Scand. B 1982, 36, 593–598.
(21) Arct, J.; Skattebøl, L.; Stenstrøm, Y. Acta Chem. Scand. B 1983, 37,
681–686.
(27) Lukin, K. A.; Zefirov, N. S.; Yufit, D. S.; Struchkov, Y. T. Tetrahedron
1992, 48, 9977–9984.
(28) Bee, L. K.; Beeby, J.; Everett, J. W.; Garratt, P. J. J. Org. Chem. 1975,
40, 2212–2214.
(22) Christl, M.; Moigno, D.; Peters, E.-M.; Peters, K.; von Schnering, H. G.
Liebigs Ann. 1997, 1791–1796.
(29) Maeda, H.; Hirai, T.; Sugimoto, A.; Mizuno, K. J. Org. Chem. 2003,
68, 7700–7706.
(23) Hiyama, T.; Kanakura, A.; Yamamoto, Y.; Nozaki, H. Tetrahedron Lett.
1978, 3047–3050.
(30) Seyferth, D.; Burlitch, J. M.; Minasz, R. J.; Mui, J. Y.-P.; Simmons,
H. D., Jr.; Treiber, A. J. H.; Dowd, S. R. J. Am. Chem. Soc. 1965, 87, 4259–
4270.
(24) Taylor, K. G.; Chaney, J. J. Am. Chem. Soc. 1976, 98, 4158–4163.
(25) Kitatani, K.; Hiyama, T.; Nozaki, H. Bull. Chem. Soc. Jpn. 1977, 50,
3288–3294.
(31) Zorin, V. V.; Kukovitskii, D. M.; Zlotskii, S. S.; Todres, Z. V.;
Rakhmankulov, D. L. J. Gen. Chem. USSR 1983, 53, 797–800.
(32) Zorin, V. V.; Kukovitskii, D. M.; Zlotskii, S. S.; Todres, Z. V.;
Rakhmankulov, D. L. J. Org. Chem. USSR 1984, 20, 785–789.
(26) Warner, P. M.; Chang, S.-C.; Koszewski, N. J. Tetrahedron Lett. 1985,
26, 5371–5374.
J. Org. Chem. Vol. 73, No. 15, 2008 5733

Eccles et al.
SCHEME 3
with DFT calculations (vide infra) allowed for structural
assignments of the individual products. Results for individual
reactions and distribution of products are shown in Table 1.
The dioxane derivative 2a showed limited solubility in ether
at the temperatures below 0 °C, and most of its reactions were
run at -10 °C at low concentrations (∼10 mM). For instance,
2a partially precipitated from 8 mM solutions at -78 °C.
Experiments with both dibromides demonstrated that the
lithium-halogen exchange reactions with 1.1 equiv of MeLi were
inefficient for the 10 mM solutions of 2, and most (∼90%) of
the starting material was recovered contaminated with <5% of
mono bromide 7.
Reactions of dioxane derivative 2a with 2.2 equiv of MeLi
at -10 °C gave the monobromo derivative 7a as the main
product accompanied by small amounts of the bromomethyl
product 8a (R ) Me), both isolated in a combined yield of
∼95% (entry 1). The same reaction run in hot ether (entry 2)
did not give the protonated product 7a, and instead the dimethyl
derivative 9a and bromo methyl 8a (R ) Me) were formed in
equal amounts as the sole products. This suggests that the
R-bromocarbanion derived from 2a in part reacts slowly with
MeBr at ambient temperature and, in part, is protonated during
workup. Some support for this scenario was provided by the
next experiment (entry 3) in which 2a was treated first with
2.2 equiv of MeLi, and after 5 min excess MeI was added at
-10 °C. No protonation product 7a was detected, and the bromo
methyl 8a (R ) Me) and dimethyl 9a were the main products
formed in an 3:2 ratio. The reaction mixture also contained about
20% of unreacted dibromide 2a, which suggests that 5 min is
insufficient time for complete lithium-halogen exchange and
that a reaction between MeLi and MeI is faster than lithiation
of 2a. With higher MeLi to 2a ratios, the dimethylated product
9a dominated and traces of another product, presumably 10a
(R ) Me), were occasionally detected.
consistent results of 20%-30% yield. We noticed, however,
low mass recovery from the reaction mixture, which was
presumably due to partial water solubility of olefin 3a or
products of dioxane ring opening. Most organic material was
recovered from the aqueous workup in the first three extractions
with benzene, and additional extractions or even continuous
extraction gave only traces of organic products. Reducing the
volume of originally31 used DMSO by substituting approxi-
mately 50% of it with benzene did not affect the yield of 3a.
While optimizing the single-step preparation of 3a, we were
simultaneously searching for an alternative method for its
preparation. In particular, we focused on reduction of vicinal
dinitroalkanes with “NiB”, which was reported to give good
yields for similar dioxane derivatives.33 Unfortunately, the
reduction of the dinitro derivative 6 under these conditions33
gave consistently low yields of about 20% of the desired olefin
3a. The preparation of 6 followed a modified literature proce-
dure32 and involved a reaction of nitrodioxane 5 and bromide
4. Thus, a lithium salt of 532 was reacted with 4 to give the
coupling product 6 in a 20% isolated yield, while 75% yield
was reported in the literature.32 Using the sodium salt of 5,
prepared in situ with NaH, did not improve the yield of 6. Higher
yields were obtained using either t-BuOK in DMSO34 (38%)
or Li Dimsyl35 (27%) as bases. The K2CO3/PTC method,
reported for coupling of nitropropane,36 gave only traces (<5%
by GC) of the coupling product 6 and the unreacted starting
material.
Bicyclohexylidene (3b) was initially obtained according to a
literature procedure for McMurry coupling of cyclohexanone.37
Since this method proved to be difficult and impractical for
multigram scale preparations, sufficient amounts of 3b were
obtained in four straightforward steps and 35% overall yield
from cyclohexanone according to a literature procedure.38
Reactions with Organolithiums. Dibromocyclopropanes 2
were treated with 1.1-6 equiv of MeLi, t-BuLi, or PhLi at -78,
-10, or 35 °C (boiling ether). After 2 h at the same or elevated
temperature, the reaction mixtures were quenched with water
and the resulting crude mixtures of products were investigated
by NMR and MS techniques. Some of the mixtures were
partially separated, and several products were isolated in the
pure form and analyzed. The collected analytical data supported
Attempts at separation of the complex mixtures into individual
components by either chromatographic methods or recrystalli-
zation were largely unsuccessful. Instead, reaction products were
identified by NMR and MS techniques, and the formation of
1a or possible bicyclo[1.1.0]butane 11a in quantities >1% can
be excluded. NMR analysis showed that all products have high
1
molecular symmetry, and the olefinic H or 13C signals were
completely absent in either crude or chromatographically
isolated mixtures of products.
Initial experiments with MeLi indicated that methylation with
MeBr of the transient R-bromocarbanion derived from 2a is
faster than the loss of bromide ion and rearrangement. To avoid
the presence of the strongly electrophilic MeBr in the reaction
mixture, we investigated reactions of 2a with PhLi and t-BuLi.
The first reagent generates the nonelectrophilic PhBr in the
lithium-halogen exchange with 2a, while t-BuLi gives t-BuBr,
which is quickly destroyed by excess t-BuLi.39
Reactions of 2a with PhLi gave an unexpected result. At a
low PhLi/2a ratio (entry 4), half of the starting dibromide reacted
giving equal amounts of the protonated anion (7a) and the
product of phenylation (!) 10a (R ) Ph), according to GC/MS
analysis. When 5 equiv of PhLi was used (entry 5), the sole
product was 10a (R ) Ph) isolated in 63% yield. GC/MS
analysis demonstrated that the reaction was complete after 10
min at -10 °C, and no intermediates were observed. Addition
of PhLi to 2a in boiling ether (35 °C) had little effect on the
reaction outcome, and 10a (R ) Ph) was formed cleanly as the
(33) Madjdabadi, A. A.; Beugelmans, R.; Lechevallier, A. Synth. Commun.
1989, 19, 1631–1640.
(34) Limatibul, S.; Watson, J. W. J. Org. Chem. 1972, 37, 4491–4492.
(35) Blakeney, A. B.; Stone, B. A. Carbohydr. Res. 1985, 140, 319–324.
(36) Makosza, M.; Kwast, A.; Kwast, E.; Jonczyk, A. J. Org. Chem. 1985,
50, 3722–3727.
(37) McMurry, J. E.; Lectka, T.; Rico, J. G. J. Org. Chem. 1989, 54, 3748–
3749.
(38) Hoogesteger, F. J.; Havenith, R. W. A.; Zwikker, J. W.; Jenneskens,
L. W.; Kooijman, H.; Veldman, N.; Spek, A. L. J. Org. Chem. 1995, 60, 4375–
4384.
(39) Seebach, D.; Neumann, H. Chem. Ber. 1974, 107, 847–853.
5734 J. Org. Chem. Vol. 73, No. 15, 2008

ReactiVity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane
TABLE 1. Product Distribution in Reactions of Dibromocyclopropanes 2 with RLi
entry
R
R-Li (equiv)
T (°C)
2
7
8
9
10
11
12
1
2
3
4
5
6
7
8
2a
X ) O
Me
Me
Me
Ph
2.2
2.2
2.2 + MeI
2.5
5
1.1
5
5.3
-10 f rt
35
-10 f rt
-10 f rt
-10 f rt or 36
-80 f -10
-10
85a
10a
45b
45a
45b
30a
20a
55b
20b
50b
20b
Ph
100 or 63c
7c
t-Bu
t-Bu
Me
50b
30c
2b
-80 f -10, or -10 f rt, or 35
∼100c
9
X ) CH2
Ph
2.5
-10 f rt
60a
40a
60b
80b
60a
25a
80a
40b, d
10b
10
11
12
13
Ph
2.5
2.5
2.5
5
35
t-Bu
t-Bu
t-Bu
-80 f -10
30a, e
50a, e
∼4a
13a
20a
-80
-80 f -10
a From NMR ratio of products in isolated mixture. b From GC/MS ratio of products in the crude mixture. c Isolated yield. d Diene 19 was isolated in
37% yield and 90% purity. e No 7a was observed at 3× higher concentration of 2b in ether.
SCHEME 4
When the same reaction was conducted at -80 °C instead
of -10 °C using a total of 6 equiv of t-BuLi, GC/MS and NMR
analysis showed significantly less of the unidentified byproduct.
Both 10a and 12a were isolated chromatographically in 6% and
27% yields, respectively, and independently characterized.
In all reactions of 2a with RLi, mass recovery of organic
products was high, often close to the theoretical amount. No
cyclopropylidene rearrangement products, neither allene 1a nor
bicyclo[1.1.0]butane 11a, were observed directly among the
reaction products. Only in reactions with t-BuLi at -10 °C could
2a form 11a as a transient species.
sole product. To demonstrate that R-phenylcarbanion 13 is
involved in the formation of 10a (R ) Ph), MeI was added to
the reaction mixture before quenching with water. In this case,
the methyl derivative 14 was formed as the only product, which
was isolated in 89% yield (Scheme 4).
In contrast to the reactivity of 2a, treatment of the
cyclohexane analogue 2b with organolithium reagents gave
bicyclo[1.1.0]butane 11b as either the exclusive (reactions
with MeLi, entry 8) or a significant (reactions with PhLi and
t-BuLi) product. Also, many of the products observed in
reactions of dioxane 2a with organolithium reagents were not
detected in the analogous reactions of 2b. The 13C NMR
spectrum of crude freshly prepared 11b showed no molecular
symmetry and no olefinic signals. During chromatographic
separation, attempted distillation, or even storage at ambient
temperature for over 1 day, 11b decomposed to form two
isomeric olefinic products in a ratio of about 4:1 (NMR). This
ratio changed to 9:1 (NMR) upon further chromatographic
purification (SiO2, hexanes). On the basis of NMR and MS
analysis, the two olefins were assigned structures 15 (major)
and 16 (minor), respectively (Scheme 5). Further support for
the assignment was provided by a close match of the NMR
spectra with those reported for the two olefins prepared by other
routes.40,41
Reactions of 2a with t-BuLi were generally less clean than
those with MeLi or PhLi. Thus, a reaction of 2a with 1.1 equiv
of t-BuLi gave a mixture consisting mostly of the starting
material and monobromide 7a in a 1:1 ratio (entry 6). When
2a was treated with 5 equiv of t-BuLi at -10 °C, all starting
dibromide 2a was consumed, and the isolated reaction mixture
(>70% of the theoretical amount) consisted of three main
products (entry 7). Two of them were identified as tert-butyl
derivative 10a (R ) t-Bu) and the debrominated product 12a
in a ratio of about 2:5 by GC/MS or 1:4 by NMR. The mixture
was partially separated giving the first fraction containing mainly
10a (R ) t-Bu), the second fraction containing mainly 12a, and
the third fraction as a mixture of 12a and the unknown
component(s) in a 2:1 ratio. Analysis of the NMR spectra of
the last fraction revealed that the unknown component(s) had
olefinic signals in the range of 111-114 and about 142 ppm,
in addition to the aliphatic signals in the high field. The olefinic
byproduct could be formed by attack of t-BuLi on the acetal
group of the dioxane ring. However, their formation by a
reaction of t-BuLi with the transient bicyclo[1.1.0]butane 11a
cannot be excluded. Monobromide 8a (R ) t-Bu) was never
observed in these reactions by GC/MS or by NMR methods.
The proposed mechanism for proton-catalyzed ring opening
in bicyclo[1.1.0]butane 11b and the formation of the dienes
(40) Yus, M.; Gutie´rrez, A.; Foubelo, F. Tetrahedron 2001, 57, 4411–4422.
(41) Lehr, R. E.; Wilson, J. M.; Harder, J. W.; Cohenour, P. T. J. Am. Chem.
Soc. 1976, 98, 4867–4875.
J. Org. Chem. Vol. 73, No. 15, 2008 5735

Eccles et al.
SCHEME 5
FIGURE 2. Three main conformers of the dioxane and cyclohexane
derivatives with R1, R2 ) H, Me, t-Bu, Ph.
setofexperimentswith2.5equivoft-BuLi,lessbicyclo[1.1.0]butane
11b was produced and lower 11b/12b ratio was observed at
-80 °C (entry 11) than when the reaction was run at -10 °C
(entry 12). When 5 equiv of t-BuLi was used (Table 1, entry
13), monobromide 7b was completely absent, and the mixture
contained bicyclo[1.1.0]butane 11b and debrominated product
12b as the sole products in about 4:1 ratio. The ratio was
practically the same whether the reaction mixture was quenched
with cold EtOH at -78 °C or poured into EtOH or water at
ambient temperature.
SCHEME 6
Finally, a competition experiment was conducted in which a
1:1 equimolar mixture of dibromocyclopropanes 2a and 2b was
reacted with 1.1 equiv of MeLi. GC/MS analysis showed that
dioxane dibromide 2a was completely consumed forming the
monobromide 7a, while only about 10% of the cyclohexyl
dibromide 2b was converted to 11b as evident from GC/MS
1
and H NMR of the crude reaction mixture.
Theoretical Analysis. To better understand the experimental
results and to support structural assignment of the observed
products, we investigated the formation and rearrangement of
several relevant carbenes, and calculated the NMR chemical
shifts for selected products at the B3LYP level of theory.
Conformational Analysis. The dioxane and cyclohexane
dispiro derivatives can exist in three main conformational forms
shown in Figure 2. Calculations at the B3LYP/6-31+G(d,p)
level for the dioxane derivatives revealed that thermodynamic
stability of the conformers follows the order B > A > C, which
parallels the trend in their net molecular dipole moments.
Conformers of type A are less stable than those of type B by
about 1.0-1.5 kcal/mol, while conformers of type C are still
less stable by an additional ∼1 kcal/mol.
shown in Scheme 5 is consistent with literature data for other
bicyclo[1.1.0]butanes and the pathways for their ring-opening
processes.10,42–44 Support for the proposed mechanism is also
provided by the occasional isolation of cyclohexanol 17
apparently formed by the hydration of the intermediate cation
18 (Scheme 5).
The reaction of 2b with PhLi at -10 °C (Table 1, entry 9)
gave the expected bicyclo[1.1.0]butane 11b and, surprisingly,
phenyl derivative 8b (R ) Ph) in approximately 2:3 ratio
(NMR). The ratio was temperature sensitive, and at higher
temperatures more bicyclo[1.1.0]butane 11b was formed. Thus,
the same reaction run at 35 °C (Table 1, entry 10) was completed
after 10 min, and the 11b/8b ratio was ∼8:1. Upon attempted
chromatographic separation of the crude reaction mixture, the
bromide completely rearranged to diene 19, which was isolated
in 37% yield. The observed facile ionization of 8b (R ) Ph)
and the formation of diene 19 is consistent with a recent report
of rearrangement of 1-bromo-2,2,3,3-tetramethyl-1-phenylcy-
clopropane in warm methanol.45 An independent experiment
demonstrated that bicyclo[1.1.0]butane 11b is stable to PhLi at
ambient temperatures for at least several hours. The ionization
of the formally cumylic bromide 8b (R ) Ph) permits a 2π
electrocyclic cyclopropane ring opening to form the allyl cation
20, which upon the subsequent elimination of a proton gives
the diene 19 (Scheme 6).
Conformers A and B of the cyclohexane derivatives appear
to have similar thermodynamic stability with a conformer of
type A being slightly favored, e.g., by 0.2 kcal/mol for 12b.
On the basis of these results, calculations of carbene formation
and subsequent rearrangement to either 1 or 11 typically
involved conformers of type B for dioxane derivatives and
conformers of type A for the cyclohexane analogues. NMR
calculations (vide infra) use the relative stability of the conform-
ers to calculate weighted average chemical shifts of selected
products. Detailed numerical information is given in the
Supporting Information.
Carbene Formation. Gas-phase calculations for anions 21
show that the loss of Br- ion and the formation of the
corresponding carbene 22 is endothermic. For the parent
cyclopropylidene 22c, the endotherm is about 20 kcal/mol (Table
2), and this energy increases by about 3.5 kcal/mol per added
cyclohexane unit to 26.8 kcal/mol for 22b.46 In contrast,
R-elimination from anion 21d containing one dioxane ring is
more endothermic by about 12 kcal/mol relative to the parent
21c and by nearly 20 kcal/mol from anion 21a containing two
Reactions of 2b with t-BuLi gave bicyclo[1.1.0]butane 11b
and smaller amounts of debrominated product 12b. In reactions
with low t-BuLi/2b ratios, monobromide 7b was also observed
in addition to 11b and 12b. The proportions of the products
depended on the amounts of the organolithium and reaction
temperature, and also varied somewhat from run to run. In one
(42) Christl, M. In AdVances in Strain in Organic Chemistry; Halton, B.,
Ed.; JAI Press; Greenwich, 1995; Vol. 4, pp 165-184.
(43) Moore, W. R.; Ward, H. R.; Merritt, R. F. J. Am. Chem. Soc. 1961, 83,
2019–2020.
(44) Nilsen, N. O.; Skattebøl, L.; Baird, M. S.; Buxton, S. R.; Slowey, P. D.
Tetrahedron Lett. 1984, 25, 2887–2890.
(46) The calculated enthalpy of 19.8 kcal/mol for R-elimination in 21c is
consistent with the exotherm of ∼17 kcal/mol measured for quenching of PhCF
with Br- in MeCN: (a) Moss, R. A.; Fan, H.; Gurumurthy, R.; Ho, G.-J. J. Am.
Chem. Soc. 1991, 113, 1435–1437.
(45) Kozhushkov, S. I.; Spa¨th, T.; Kosa, M.; Apeloig, Y.; Yufit, D. S.;
deMeijere, A. Eur. J. Org. Chem. 2003, 4234–4242.
5736 J. Org. Chem. Vol. 73, No. 15, 2008

ReactiVity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane
TABLE 2. Calculated Energies for the Formation of Carbenes in
the Gas Phasea
SCHEME 7
Addition of dioxane rings to 23c has a more pronounced effect
on the enthalpy of elimination. Thus, the first dioxane ring
increases the enthalpy of complex elimination by nearly 5 kcal/
mol in 23d. Intramolecular coordination of the Li+ ion by the
ring’s oxygen atoms in 23d moderately stabilizes the salt, and
consequently, the enthalpy of elimination increases by 0.7 kcal/
mol. Addition of the second dioxane ring increases this enthalpy
by 5 kcal/mol in 23a in which the Li+ ion is internally
coordinated. Free energy change for these reactions is shown
graphically in Figure 3. Interestingly, coordination of the Li+
ion to dioxane’s oxygen atoms decreases the endergonicity of
the complex elimination in spite of increased endotherm of the
reaction. This is due to lowering of entropy of 23d by 7 cal/
mol·K upon intramolecular coordination of the Li+ ion.
The results demonstrate that the dioxane salt 23a is more
stable toward elimination and carbene formation than the
cyclohexane analogue 23b by about 5 kcal/mol.
Stabilization of carbenes by coordination to a molecule of
ether appears to be modestly exothermic for cyclopropylidene
22c forming 24c, but due to the significant entropy decrease
(-38 cal/mol ·K) the process is still endergonic at this level of
theory (Scheme 7). This small energy gain in stabilization of
22c is insufficient to offset the 15.6 kcal/mol endotherm of the
elimination of the LiBr complex from 23c, and the whole
process is significantly endergonic due to the net negative
entropy change. Calculations at the MP2/6-31+G(d,p)//B3LYP/
6-31+G(d,p) level with the DFT thermodynamic corrections
lower this energy by 7.7 kcal/mol, and the resulting free energy
change for the formation of 24c from carbene 22c is nearly
zero.47 This suggests that complex 24c is in equilibrium with
carbene 22c, and the calculations for the free carbene in gas
phase provide a reasonable approximation of the solution
reactivity.
b
a B3LYP/6-31+G(d,p) level of theory. The Li+ interacts with the
c
ring’s oxygen atoms. The Li+ does not interact with the ring’s oxygen
atoms.
The optimized geometry of the parent salt 23c converged at
the Cs point group symmetry (Figure 4). The Me2O, Li, and Br
lie in the symmetry plane, which is orthogonal to the cyclo-
propane ring. The Me2O and cyclopropane fragments are
connected by the Li+ ion, which is also coordinated to the Br
atom. The resulting CsLi· · ·OMe2 and CsLi· · ·Br angles are
171° and 130°, respectively. The Li · · ·OMe2 and Li-C distances
(1.89 Å and 1.96 Å, respectively) found in the parent salt 23c
are approximately constant in the series of salts 23, while the
Br-C and Br · · ·Li distances vary in response to the structural
changes.
The C-Br distance, dC-Br, in the parent salt 23c (2.22 Å) is
practically unchanged, and the Br · · ·Li separation (2.44 Å) is
shortened by 0.01 Å upon appending the cyclohexane rings. In
contrast, the dC-Br decreases by 0.06 Å with simultaneous
increase of the Br · · · Li distance by 0.03 Å upon appending
the first dioxane ring in 23d. Moving the lithium atom toward
the dioxane oxygen atoms in 23d trades the coordination
of the cation by the bromine atom (dLi Br ) 2.94 Å) for the ring
oxygen atom (dLi O ) 2.14 Å) and leads to the contraction of
FIGURE 3. Relative energies for the formation of carbene 22 from
anion 21 (black, reaction 1) and from salt 23 (gray, reaction 2). The
empty bar represents data for 23d in which Li+ is not coordinated to
the dioxane ring. For reaction schemes, see Table 2.
dioxane rings. The entropy change in the reaction is about 30
cal/mol·K, which lowers the free energy change by almost 9
kcal/mol. The graphical representation of free energy change
in the process is shown in Figure 3.
Salts of the anions 23 in which the lithium ion is coordinated
to a molecule of Me2O are more realistic models for solution
processes. Calculations for the formation of carbenes 22b from
23 revealed a smaller endotherm for the LiBr·2Me2O complex
elimination as compared to the elimination of Br- from 21
(Table 2). The enthalpy of the elimination reaction increases
for each added cyclohexane ring relative to the parent 23c and
for 23b the energy is higher by 3.8 kcal/mol.
(47) A reliable theoretical description of the stability of a dative bond such
as that in 24c is provided by the MP2 method.
J. Org. Chem. Vol. 73, No. 15, 2008 5737

Eccles et al.
FIGURE 4. Optimized (B3LYP/6-31+G(d,p)) geometries of ground- and transition-state structures for selected molecules with indicated selected
interatomic distances and angles.
FIGURE 5. Representation of the FMO contours obtained at the
B3LYP/6-31+G(d,p) level of theory for the cyclopropylidene (22c).
the C-Br distance by 0.08 Å. In the bisdioxane salt 23a in
which the Li+ ion is also internally coordinated, the C-Br
distance is further reduced by 0.01 Å and the Li-C separation
is slightly enlarged to 2.00 Å. Overall, the C-Br distance in
23a is shorter by 0.15 Å than that in cyclohexane analogue 23b.
FIGURE 6. Absolute and relative energies of the LUMO and HOMO
obtained at the B3LYP/6-31+G(d,p) level of theory for a series of
carbenes. For 22c, EHOMO ) -6.56 eV and ELUMO ) -2.85 eV.
A similar trend in the shortening of the C-Br distance, dC-Br
,
upon addition of dioxane rings in salts 23 is also found for the
bromo anions 21d and 21a. Thus, in 21d the dC-Br decreases
by 0.04 Å relative to the parent 21c and by an additional 0.03
Å (to 2.09 Å) in 21a. For the cyclohexane analogues 21e and
21b the dC-Br decreases by about 0.01 Å per added ring.
The observed trends in the Br-C bond lengths in both series
of compounds 21 and 23 parallel the trends in the energetics of
the carbene formation from the two substrates.
the parent 22c (+0.19), while in the dioxane analogues 22d
and 22a the charge is higher (+0.21). Interestingly, the
orientation of the cyclopropylidene with respect to the dioxane
ring has a significant effect on the properties of the carbene.
For the equatorial orientation of the carbenic center in 22d-eq,
the LUMO is lower by 0.19 eV than in the axial conformer
22-ax, while the enthalpy difference between the two conformers
is only 0.15 kcal/mol. This suggests that stereoelectronic
interactions (such as those in the anomeric or gauche effects)
exist between the oxygen atoms and the carbenic center.
Carbene Electronic Properties. Analysis of NBO wave
functions for the series of carbenes 22 shows that the HOMO
involves an sp0.5 hybridized orbital of the carbenic atom, while
the LUMO is essentially a pure p orbital orthogonal to the
cyclopropylidene ring (Figure 5). The energies of the LUMO
and HOMO orbitals are gradually increasing upon substitution
with the cyclohexane rings. In contrast, the LUMO, which is
responsible for the electrophilic properties, gradually decreases
in the series of dioxane analogues, while the HOMO remains
practically unchanged (Figure 6). Thus, addition of the cyclo-
hexane rings increases nucleophilic properties of the carbene,
while dioxane rings enhance its electrophilic properties, which
is consistent with the general trend in philicity of carbenes and
their reactivity with alkenes.48 This conclusion for carbenes 22
is further supported by an analysis of the charge density, which
demonstrated that the carbenic center retains approximately the
same charge for the cyclohexane derivatives, 22b and 22e, and
Carbene Rearrangement. Investigation of the rearrangement
of two singlet carbenes 22a and 22b revealed that the formation
of either the corresponding allenes 1 or bicyclo[1.1.0]butanes
11 is a highly exothermic process characterized by a relatively
(48) Moss, R. A. In Carbene Chemistry; Bertrand, G., Ed.; Marcel Dekker:
The Netherlands, 2002; pp 57-101.
5738 J. Org. Chem. Vol. 73, No. 15, 2008

ReactiVity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane
TABLE 3. Calculated Thermodynamic Parameters for Rearrangement of Cyclopropylidenea
a MP2/6-31+G(d,p)//B3LYP/6-31+G(d,p) level of theory with DFT thermodynamic corrections. Symmetry of the starting carbenes: 22a-Cs, 22b-C2,
22c-C2v, 22f-C2. b This value is consistent with that obtained with the CCSD//CASSCF (3.6 kcal/mol) or CCSD//CISD (4.2 kcal/mol) methods (ref9)
and is lower by 1.3 kcal/mol than that calculated at the DFT//DFT level of theory.
low e11 kcal/mol activation energy (Table 3). The calculated
∆Gq298 values are greater for the dioxane carbene 22a than for
the analogous transformations of the cyclohexane analog 22b.
A comparison of the calculated activation energies with those
for two model carbenes, the parent cyclopropylidene (22c) and
tetramethylcyclopropylidene (22f), is particularly informative
(Table 3). Thus, activation energies for the rearrangement of
the cyclohexane and tetramethyl carbenes, 22b and 22f, to the
corresponding allenes are similar and nearly 5 kcal/mol higher
than that obtained for the transformation of the parent cyclo-
propylidene (22c) to allene 1c. This significant increase of
electronic effects of the group adjacent to the -CH2- in the
carbene 22. Thus, replacement of a hydrogen atom in the methyl
of 22f with alkyl in 22b lowers the ∆Hq by 0.8 kcal/mol, while
the substitution of an alkoxy for hydrogen in 22a increases the
∆Hq by 2.8 kcal/mol.
The difference between the free energies of activation ∆Gq
for the two competing rearrangements of carbenes 22 is >4
kcal/mol, which suggests that bicyclo[1.1.0]butanes 11 are
practically the only expected products. The calculated low
activation energies for the C-H insertion process (<6.0 kcal/
mol) further suggests that the rearrangement of 22 to 11 should
be observed even at low temperatures. The fact that only
rearrangements of 22b to 11b and 22f to 11f10,11 are observed
experimentally indicates the difficulties with the formation of
the dioxane carbene 22a, which is consistent with the compu-
tational results for anions 21 and 23.
Analysis of the transition-state geometry for the allene
rearrangement revealed that the tetramethyl and cyclohexane
structures 1f-TS and 1b-TS have the Cs symmetry and the
shortest in the series C(2)· · ·C(3) distances of 1.778 and 1.834
Å (Figure 4), respectively. In contrast, transition states 1c-TS
and 1a-TS are asymmetric, and the degree of deviation from
the Cs geometry follows the trend in the C(2) · · ·C(3) separation.
Thus, for 1a-TS with the C(2) · · ·C(3) distance of 1.848 Å the
parameters50 δ1 and δ2 are small (6° and 12°) and they increase
to 12° and 17° for 1c-TS for which the C(2) · · ·C(3) is the
longest (1.995 Å). This is consistent with the extensive analysis
∆Gq for 22b and 22f and also 22a (about 7 kcal/mol) is
298
contrary to expectations based on results for cis-2,3-dimethyl-
cyclopylidene8 and is presumably related to steric interaction
of the four substituents in the ring opening TS.
Further inspection of the computational results for both
carbenes 22a and 22b shows that the formation of bicyclo[1.1.0]-
butanes 11 is significantly easier (kinetic products) than the
rearrangement to the corresponding allenes 1, which are the
thermodynamic products. The calculated activation enthalpy for
the C-H insertion process in all three carbenes 22 is in the
range of 1-4.6 kcal/mol, which is consistent with activation
energies calculated for the insertion of methylene to methane
and ethane at a similar level of theory.49 The order of the
calculated ∆H‡ values, 22b < 22f < 22a, appears to reflect the
(49) Bach, R. D.; Su, M.-D.; Aldabbagh, E.; Andre´s, J. L.; Schlegel, H. B.
J. Am. Chem. Soc. 1993, 115, 10237–10246.
J. Org. Chem. Vol. 73, No. 15, 2008 5739

Eccles et al.
1
calculated and experimental H and 13C NMR chemical shifts
(Figure 8). The theoretical chemical shifts used for the correla-
tion were obtained as weighted averages of chemical shifts for
2-4 major conformers for each compound. For dioxane
derivatives, the predominant conformers are of type B (Figure
2), while for the cyclohexane analogues both conformers of type
A and B are populated to a similar degree.
1
Structural assignment of the experimental H and 13C NMR
data for the comparison with the theoretical values was made
on the basis of general trends in chemical shifts, coupling
constant values (1H data), relative intensities of the signals, and
DEPT results (11b). For the two cyclohexane derivatives 11b
and 12b, the ambiguous 13C data for CH2 groups was compared
FIGURE 7. Strain energy (SE) calculated from SCF energies at the
B3LYP/6-31+G(d,p) level of theory using a homodesmotic reaction.
Experimental SE for the parent bicyclo[1.1.0]butane taken from ref 52
1
for the parent cyclopropylidene,9 according to which the ring
opening process initially follows the disrotatory symmetric
motion of the two CR2 groups characteristic for a 2e concerted
process. In the vicinity of the TS one of the CR2 groups begin
to rotate faster destroying the Cs symmetry. For the parent
cyclopropylidene 1c, this asymmetric motion begins at about
1.85 Å,9 which is consistent with the observed symmetric TS
for cyclohexane 1b-TS (1.834 Å) and asymmetric TS for
dioxane 1a-TS (1.848 Å).
The intramolecular insertion of carbene into the C-H bond
and the formation of the bicyclo[1.1.0]butane derivative 11 is
a concerted process49 in which the vacant p orbital interacts
with the C-H bond, while the hydrogen moves to the carbenic
sp0.5-hybridized orbital. In the transition state for rearrangement
of both 22a and 22b, the C-H is elongated by about 0.15 Å
and the H · · ·C(1) distance is about 1.5 Å. The C(1) · · ·C distance
is about 1.95 Å. The C-C bond formation and the hydrogen
transfer are both more advanced in the cyclohexane 11b-TS by
about 0.04 Å than in the dioxane 11a-TS.
Strain Energy (SE). Strain energies (SEs) for the two
bicyclo[1.1.0]butanes, the expected 11a and the observed 11b,
were obtained using a homodesmotic reaction51 and compared
to that of the parent bicyclo[1.1.0]butane. The results shown in
Figure 7 demonstrate that the SE for the cyclohexane derivative
11b is identical to that obtained for the parent, which in turn is
close to that obtained from experimental heats of formation.52
The SE for the dioxane derivative 11a is lower by 6 kcal/mol
than that of 11b. However, considering that analogous calcula-
tions for [1,3]dioxane give SE of -2 kcal/mol, the overall strain
of 11a is similar to that of the cyclohexane derivative 11b.
Analysis of the molecular geometry for the three bicyclo[1.1.0]-
butanes showed no unusual differences, except for the length
of central C-C bond. It is longer for 11a (1.509 Å) than for
cyclohexane 11b (1.500 Å) and for the parent (1.494 Å).
NMR Structural Assignment. Among 10 primary and 5
secondary products of reactions of 2a and 2b with RLi, 5 were
isolated in their pure forms. The remaining compounds were
analyzed as mixtures, and their structural assignment was based
on MS and NMR spectra, comparison with literature NMR
spectra (12b, 15, and 16), or close match with analogous
cyclopropane derivatives53–56 (bromine-containing derivatives,
2, 7, 8, and also 9a; details in the Supporting Information).
Further support for the structural assignment to the observed
products that do not contain bromine (9a, 10a (R ) Me, Ph,
t-Bu), 11, and 12) was provided by comparison of the DFT-
to the best matching theoretical values. Most of the H NMR
data for 11b and 12b could not be unambiguously matched with
the calculated values, and therefore, only a few distinct signals
were used for the correlation. Thus, only the cyclopropane CH2
signal of 12b was used in Figure 8a, although the position of
the maximum of the overlapping multiplets at 1.43 ppm is in
excellent agreement with the weighted average for the calculated
1H chemical shifts (1.44 ppm). The results are shown in Figure
8, and numerical data is provided in the Supporting Information.
Correlations presented in Figure 8 generally show good
agreement between the theoretical and experimental values. The
biggest differences between the two sets of data are observed
1
for the cyclopropane ring. Thus, the results show that the H
signals of the cyclopropane CH group in dioxane derivatives
are systematically underestimated by about 0.2 ppm with a
maximum of 0.28 ppm for 12a. Calculations also systematically
overestimated the 13C chemical shifts for the spiro C atoms of
the dioxane derivatives by about 3 ppm, and for the other
cyclopropane ring C atom a substantial overestimation by -4.6
ppm was found for 9a. Chemical shifts of both carbon atoms
of the cyclopropane ring in 12b are underestimated by 6.5 and
2.5 ppm.
Discussion
Experimental results show that dibromocyclopropane 2b
reacts with alkyllithiums as expected giving the rearrangement
product 11b, while the dioxane derivative 2a gives only
substitution products and no rearrangement. Reaction pathways
observed for both substrates are summarized in Scheme 8.
The cyclohexane derivative 2b smoothly forms the lithium
salt 23b upon treatment with MeLi, which subsequently
undergoes elimination of LiBr. The resulting carbene 22b (or
carbenoid) rearranges to bicyclo[1.1.0]butane 11b in a nearly
quantitative yield. The step of LiBr elimination is fast even at
low temperature, and no methylation products are observed. This
indicates that reaction rates for elimination are greater than
alkylation (k2b . k5b and k2b . k6b in Scheme 8) and also that
the rate for C-H insertion is greater than rearrangement to allene
1b (k4b . k3b). The latter is consistent with the computed lower
free energy of activation for the formation of 11b than for the
formation of allene 1b by 6.4 kcal/mol (Table 3) and with
reports of the preferential formation of bicyclo[1.1.0]butanes
by some other tetrasubstituted gem-dibromocyclopropanes.10,11,14
(53) Inoue, A.; Kondo, J.; Shinokubo, H.; Oshima, K. Chem. Eur. J. 2002,
8, 1730–1740.
(50) Parameters δ are 0° for Cs-symmetric geometry and 90° for D2d allene.
For the definition, see ref 9.
(54) Wijsman, G. W.; deWolf, W. H.; Bickelhaupt, F. Recl. TraV. Chim.
Pays-Bas 1994, 113, 53–59.
(51) George, P.; Trachtman, M.; Bock, C. W.; Brett, A. M. Tetrahedron 1976,
32, 317–323.
(55) Bowry, V. W.; Lusztyk, J.; Ingold, K. U. J. Am. Chem. Soc. 1991, 113,
5687–5698.
(52) Wiberg, K. B. Angew. Chem., Int. Ed. 1986, 25, 312–322.
(56) Warner, P. M.; Le, D. Synth. Commun. 1984, 14, 1341–1347.
5740 J. Org. Chem. Vol. 73, No. 15, 2008

ReactiVity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane
1
FIGURE 8. Correlation between calculated (B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d,p)) and experimental H (a) and 13C NMR (b) chemical
shifts δ for selected compounds. Best fit functions: δcalcd ) 0.999(5) × δexp (r2 ) 0.996) and (b) δcalcd ) 1.007(7) × δexp (r2 ) 0.994).
explained as a coupling of a caged radical pair57 that is formed
SCHEME 8
during the metal-halogen exchange (MHE) process in ac-
cordance with a general mechanism58 involving a single electron
transfer (SET) process (Scheme 9). The proposed mechanism
for the formation of 8b is consistent with the observations that
(i) the amount of 8b appears to be greater at lower temperatures
and at lower concentrations and (ii) no other byproduct are
observed in significant amounts.
A reaction of the dioxane dibromide 2a with PhLi proceeds
differently than that of the cyclohexane analog. In this case,
the initially formed bromoanion 23a apparently undergoes a
facile nucleophilic substitution with excess PhLi to give salt
10a-Li, which is either protonated to give 10a or methylated
with MeI to give 14 as the exclusive products. This indicates
again that the rate for LiBr elimination from 23a to form carbene
22a is significantly lower than those for the competing processes,
SCHEME 9
including a reaction of the anion with PhLi (k6a . k2a, Scheme
8). It may appear that the observed product 10a-Li is formed
according to a metal-assisted ionization (MAI) of the C-Br
bond in the anion 23a as it was postulated for vinyl R-haloan-
ions59 and later for some cyclopropyl R-haloanions.26,60 The
computational results show however, that there is no significant
loosening of the C-Br bond in the dioxane derivative 23a as
postulated in MAI and experimentally observed for some
carbenoids.18 Instead, the C-Br bond in 23a is shorter by 0.15
Å than that in the cyclohexane analogue 23b. Moreover, the
Li+ ion is coordinated to the ring’s oxygen atoms, which opens
the carbon center for nucleophilic attack. Therefore, a more
appropriate description for the process observed in 2a should
be coordination-assisted nucleophilic substitution (CANS) as
shown in Figure 9. Interestingly, this mechanism does not seem
to operate for reactions of 2a with MeLi, presumably due to
the presence of MeBr. The observation of bromide 8a (R )
Me) in reactions with MeLi (Table 1) as the primary product
indicates that in this case k5a > k6a. The formation of methylation
byproduct (analogues of 8-10) and also bicyclopropylidenes
(products of self-condensation) in reactions of some dibromocy-
In contrast, salt 23a derived from dioxane derivative 2a and
MeLi undergoes efficient methylation with MeBr to yield 8a.
This indicates that k2a , k5a for the dioxane derivative and also
that the activation energy for LiBr elimination is significantly
higher than that for methylation of the anion. Assuming that
the rates of methylation of either anion 23a or 23b are similar
(k5a ∼ k5b), the rate of LiBr elimination from the former is
significantly lower than that from the cyclohexyl derivative 23b
(k2a , k2b). This is consistent with the computed higher
endergonicity for the formation of carbene 22a by nearly 5 kcal/
mol than the formation of 22b from the respective salts 23
(Table 2). In the presence of excess MeLi, bromide 8a undergoes
Li-halogen exchange, and the resulting anion 10a- is methy-
lated again giving the dimethyl derivative 9a.
Reactions of dibromides 2a and 2b with PhLi gave surprising
results highlighting again the differences in the reactivity of
the two compounds. Thus, reactions of the cyclohexane dibro-
mide 2b with PhLi gave the expected bicyclo[1.1.0]butane
derivative 11b, but, surprisingly also the bromide 8b (R ) Ph)
was formed as the only byproduct. The formation of 8b can be
(57) Ward, H. R.; Lawler, R. G.; Loken, H. Y. J. Am. Chem. Soc. 1968, 90,
7359–7360.
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1986, 108, 7435–7436.
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J. Org. Chem. Vol. 73, No. 15, 2008 5741

Eccles et al.
of these two products, 10a and 12a, indicates that k7a > k6a.
There is no clear evidence for the generation of carbene 22a,
although it cannot be excluded that some of the unidentified
byproduct(s) are derived from a reaction of t-BuLi with the
transient bicyclo[1.1.0]butane 11a.
Overall, elimination of LiBr from anion 23a and the formation
of carbene 22a (or a carbenoid) appears to be the slowest process
among all possible pathways in the transformation of 2a, at least
with MeLi and PhLi. The lithium salt 23a is stabilized by nearly
5 kcal/mol over salt 23b and appears to exhibit dual philicity:
it reacts with electrophiles such as MeBr or, in their absence,
with nucleophiles such as PhLi.
FIGURE 9. Proposed configuration for metal-assisted ionization
(MAI)59 and coordination-assisted nucleophilic substitution (CANS).
See the text for details.
SCHEME 10
The origin of the observed difference in reactivity of the two
cyclopropanes 2a and 2b lies primarily in the electronic structure
of the carbenes 22a and 22b and, to some extent, in the ability
of the dioxane rings to chelate the Li+ ion. Analysis of the three
carbenes 22a-c shows significantly more electrophilic character
of the dioxane carbene 22a due to the inductive effect of the
-CH2O- groups. This is evident from the higher positive
charge of the carbenic center and lower energy of the LUMO.
This in turn, results in tighter bonding to an electron donor Br-,
as evident from the C-Br bond length in the anions 21 and Li
salts 23, and less favorable R-elimination process in 21a and
23a. Consistent with this view is the observed slow addition
of:CBr2 to olefin 3a, and also fast reactions of dibromide 2a
with RLi (k1a > k1b), as compared to the cyclohexane analogues.
The rigidity of the molecular skeleton and the orientation of
oxygen atoms relative to the carbenic center are not optimal
for the effective chelation of Li+ in 23a. Therefore, this internal
coordination provides only a modest additional enthalpic
stabilization of 23a, which is compensated by the entropy
decrease. It results, however, in moving the Li+ ion away from
the carbanion center and exposing it to both electrophiles and
nucleophiles. In other dibromocyclopropanes, containing either
flexible or better aligned substituents, such as methoxy,23
alkoxymethyl,17,64 acetal,21,24,65–67 alkylthiomethyl,20,68 and
dialkylaminomethyl,69,70 the heteroatom can effectively chelate
the Li+ ion increasing the overall stability of the salt and
directing the insertion reaction.71 These single substituents,
however, do not significantly affect the carbenic center, and
the formation of carbenes (carbenoids) and their subsequent
reactions (insertion or rearrangement) are the dominant pro-
cesses. This is in sharp contrast to our results for 2a, and, to
our knowledge, there is no other dibromocyclopropane that is
resistant to the carbene formation. In this sense dibromocyclo-
propane 2a is an exceptional compound.
clopropanes with MeLi has been reported in the literature,2,22,61–63
but always as minor components of mixtures of products.
Results for reactions of dibromides 2a and 2b with t-BuLi
are consistent with those obtained with MeLi and PhLi, although
they are complicated by the presence of t-BuBr formed in the
metal-halogen exchange process. In the reactions of dibromide
2b with t-BuLi, the bicyclo[1.1.0]butane 11b is still the
dominant product, but is accompanied by debrominated product
12b formed regardless of the reaction and quenching process
temperatures. The formation of 12b can be rationalized as a
competition between the R-bromo anion 23b and t-BuLi for
the proton from t-BuBr (Scheme 10) on one hand, and Br-
elimination and the formation of carbene (carbenoid) 22b on
the other. Since the lithium-halogen exchange is a fast process,
the t-BuLi that is being added dropwise to 2b is rapidly
consumed leaving anion 23b and t-BuBr. Thus, at the beginning
of t-BuLi addition the concentration of anion 23b is greater than
that of t-BuLi, and 23b may effectively compete for the proton
from t-BuBr. At low temperature, the elimination of Br- and
theformationofcarbene22bisslow,andlessbicyclo[1.1.0]butane
11b is formed in favor of 7b (Table 1, entry 12). At higher
temperatures (-10 °C), the formation of carbene (carbenoid)
and its subsequent rearrangement to bicyclo[1.1.0]butane 11b
is the dominant process, and less monobromide 7b is generated
(Table 1, entry 11). With the low t-BuLi/2b ratio, the excess
t-BuLi is never achieved and monobromide 7b is formed in
significant quantities. For the high t-BuLi/2b ratio, the generated
monobromide 7b is lithiated with excess t-BuLi that is built up
at the end of the addition process, and the resulting anion 12b-
is protonated during the workup. Thus, on the basis of the
product distribution (Table 1), it can be postulated that at low
temperatures k2b < k7b (entry 12) and at higher temperatures
k2b > k7b (entry 11). At high t-BuLi/2b ratio, excess t-BuLi
completely transforms 7b to anion 12b-, which subsequently
gives 12b. Better understanding and support of this proposed
mechanism require further detailed experimental studies.
Reaction of dibromide 2a and t-BuLi also gives the debro-
minated product 12a among unidentified product(s) arising
presumably from the low stability of the [1,3]dioxane ring
toward the base. The formation of 12a can be envisioned to
occur in a way analogous to that of the generation of 12b from
2b. The initially formed anion 23a is protonated with t-BuBr
to form 7a, which is further converted to 12a. In addition, some
of the anion 23a apparently undergoes substitution reaction
(CANS) with t-BuLi giving 10a (R ) t-Bu). The distribution
Conclusions
The reactions of two dibromocyclopropanes 2a and 2b with
three different organolithium reagents revealed several mecha-
nistic pathways, which depend on the substrate and the
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5742 J. Org. Chem. Vol. 73, No. 15, 2008

ReactiVity of 13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane
in free energy and used to calculate weighted shielding tensor
for each nucleus, which was converted to NMR chemical shifts
using cyclohexane as the reference. More details are listed in
the Supporting Information.
organolithium. The cyclohexane derivative 2b reacts as expected
to form carbene 22 (or carbenoid), which undergoes rearrange-
ment to 11b. In contrast, the anion derived from 2a is unusually
stable and undergoes either alkylation with MeBr (electrophilic
substitution) or arylation with PhLi (nucleophilic substitution)
as the main or exclusive reaction pathways. This significant
resistance to the R-elimination process in anion 23a is ascribed
to the cumulative effect of four -CH2O- groups, rather than
to the intramolecular coordination of the Li+ ion by the ring
oxygen atoms. Calculations for a series of anions indicate that
the dioxane ring increases the electrophilic character of the
cyclopropylidene by lowering the LUMO, which retards the
R-elimination process. The effect is approximately additive for
each dioxane group. A comparative analysis of the literature
data indicates that a single -CH2O- or -CH2N< substituent
does not noticeably impact the reactivity of dibromocyclopro-
panes and their intermediates.
Overall, the electron withdrawing effect of the four -CH2O-
groups results in the enhanced electrophilicity of carbene 22a
and manifests itself in (i) the resistance of the anion 23a to the
elimination of LiBr, (ii) slow addition of :CBr2 to olefin 3a,
and (iii) in fast reactions of dibromide 2a with RLi (k1a > k1b),
as compared to the cyclohexane analogues.
Future studies of carbene 22a and its rearrangement to 1a
and 11a will require a different precursor such as the appropriate
diazo derivative.
Experimental Details
Melting points are uncorrected. NMR spectra were recorded at
either 300 MHz (1H) and 75 or 100 MHz (13C), respectively, in
CDCl3, unless otherwise specified. Chemical shifts were referenced
to TMS (1H) or solvent (13C).
13,13-Dibromo-2,4,9,11-tetraoxadispiro[5.0.5.1]tridecane
(2a). Method A. A 50% aq solution of NaOH (10 g, 125 mmol)
was added dropwise at room temperature to a vigorously stirred
solution of olefin 3a (3.45 g, 20 mmol), CHBr3 (5.5 mL, 60
mmol), and TEBA (50 mg, 0.2 mmol) in CH2Cl2 (25 mL). After
12 h, no more progress was observed by GC/MS, and additional
portions of CHBr3 (5 mL) and TEBA (50 mg) were added. The
stirring was continued for 3 days during which two additional
portions of CHBr3 and TEBA were added. The reaction mixture
was filtered through Celite, which was washed with CH2Cl2 (200
mL). The organic layer was separated, dried (NaSO4), and
concentrated. Excess CHBr3 was distilled off under reduced
pressure. The resulting mixture of starting material and product
(1:4 ratio by 1H NMR) was separated by column chromatography
(CH2Cl2/EtOAc, 10:1). The isolated product (2.5 g) was
recrystallized from EtOH, giving 1.80 g (33% yield) of 2a as
colorless crystals (mp 162-166 °C). Alternatively, dibromide
2a was dried in vacuum (P2O5) and then sublimed at 125 °C/
1
1.0 Torr giving a white solid: mp 163.5-164 °C; H NMR δ
Computational Details
3.99 and 4.04 (AB, J ) 12.0 Hz, 8H), 4.90 and 4.92 (AB, J )
6.2 Hz, 4H); 13C NMR δ 32.0, 40.7, 68.9, 94.1; IR (neat) 1147
(C-O) cm-1; MS m/z 235 and 233 (1:1, 1), 86 (63), 65 (100);
HRMS calcd for C9H13Br2O4 342.9181, found 342.9199. Anal.
Calcd for C9H12Br2O4: C, 31.42; H, 3.52. Found: C, 31.63; H,
3.50.
Quantum-mechanical calculations were carried out with the
B3LYP72,73 and MP2(fc)74methods using the Gaussian 98 pack-
age.75 Geometry optimizations were performed with the DFT
method using either the 6-31+G(d,p) or 6-31G(d,p) (for NMR
analysis) basis sets, appropriate symmetry constraints, and default
convergence limits. Transition states were located using the QST3
keyword. The guess for the TS geometry was generated by
optimizing the geometry with the C2-C3 distance frozen at 1.85
Å for allene formation, and C1-CR, C1-HR, and CR-HR
distances frozen at 1.95 Å, 1.33 Å, and 1.32 Å, respectively.
Carbenes were considered in their singlet states.
Method B. Following a general procedure,30 PhHgCBr3 (13.7
g, 26 mmol) was added in one portion to a stirred solution of
olefin 3a (3.0 g, 17 mmol) in dry benzene (30 mL) under
nitrogen. The reaction mixture was heated to 85 °C for 5 h. The
solid precipitate was filtered, and the filtrate was concentrated.
The resulting mixture of starting material 3a and product 2a
1
(1:1 by H NMR) was separated as above giving 1.60 g (28%
Vibrational frequencies obtained with the DFT method were
used to characterize the nature of the stationary points and to
obtain thermodynamic parameters. Zero-point energy (ZPE)
corrections were scaled by 0.9806.76 Population analysis was
obtained using the NBO algorithm77 supplied in the Gaussian
package. For rearrangement of carbenes, single-point energies
were calculated with the MP2 method without the BSSE
correction. Following general recommendations,78 isotropic
magnetic shielding tensors were calculated for major conformers
of each compound with the GIAO method at the B3LYP/6-
311+G(2d,p)//B3LYP/6-31G(d,p) level of theory. Population of
each conformer was established from the calculated differences
yield) of 2a.
13,13-Dibromodispiro[5.0.5.1]tridecane (2b). The dibromide
was obtained from olefin 3b as described for 2a in method A
without additional portions of CHBr3, base or catalysts. The
crude product was passed through a silica gel plug, recrystallized
(isooctane), and sublimed (70 °C at 1.5 Torr) giving 71% yield
1
of the dibromide 2b as colorless crystals: mp 101-102 °C; H
NMR δ 1.37-1.74 (m); 13C NMR δ 24.9, 25.8, 30.9, 35.3, 56.8;
MS m/z 256 and 254 (M - Br, 1:1, 31), 175 (M - 2 Br, 100).
Anal. Calcd for C13H20Br2: C, 46.46; H, 6.00. Found: C, 46.51;
H, 6.07.
Reaction of 2 with Organolithium. General Method. To a
stirred solution of dibromide 2 (typically 0.7 mmol) in dry ether
(50-70 mL), the appropriate amount of 1.2 M MeLi in ether, 2.0
M PhLi in dibutyl ether, or 1.7 M t-BuLi in pentane was added
dropwise at -78, -10, or 36 °C under argon. After the addition
was complete, the reaction mixture was placed in an ice-salt bath
(-10 °C) or allowed to warm to ambient temperature. Alternatively,
MeLi or PhLi were added to a solution of 2 in boiling ether. After
2 h, the reaction mixture was quenched with degassed water
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J. Org. Chem. Vol. 73, No. 15, 2008 5743

Eccles et al.
(0.25-0.5 mL), the aqueous layer was separated, and the organic
and NASA GSRP (NGT-8-52927, WE). We thank Dr. Krystyna
K. Kulikiewicz for her assistance with the preparation of 3a.
1
layer was concentrated. H NMR, 13C NMR, and GC/MS were
taken of the crude mixture. Products were purified and partially
separated by column chromatography and/or sublimation. Detailed
procedures and analytical data are provided in the Supporting
Information.
Supporting Information Available: Full experimental details
for 3-12, NMR spectra for reaction products, and computational
results. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. Financial support for this work was
received from the PRF (37174-AC1), NSF (OISE 0532040, MJ),
JO800054P
5744 J. Org. Chem. Vol. 73, No. 15, 2008