Spirodiepoxides: Heterocycle synthesis and mechanistic insight

Article abstract of DOI:10.1002/anie.200701401

(Chemical Equation Presented) In concert but out of sync: Reactions of spirodiepoxides (SDEs) with an amide, amidine, and thioamide and the first crystal structure of an SDE are reported (see scheme for reaction with amide; DMDO = 2,2-dimethyldioxirane).

Full text of DOI:10.1002/anie.200701401

Communications
DOI: 10.1002/anie.200701401
Reaction Mechanisms
Spirodiepoxides: Heterocycle Synthesis and Mechanistic Insight**
Stephen D. Lotesta, Sezgin Kiren, Ronald R. Sauers, and Lawrence J. Williams*
The spirodiepoxide (SDE) functional group has emerged as
an electrophile with potential applications in synthesis.[1–10]
Sequential allene oxidation gives SDEs. Nucleophilic SDE
opening effectively translates the three-carbon axis of chir-
ality of the allene into a densely functionalized motif: two
differentially functionalized stereogenic centers separated by
a ketone. To be applied generally, nucleophiles that effect
SDE opening must continue to be identified, a general
method for the stereoselective formation of SDEs must be
developed, and a mechanistic understanding of nucleophilic
opening must be established. This report is focused on new
mechanistic insight gained through investigations on the
formation of heterocycles from SDEs. We relate herein the
formation of azoles from SDEs, the first crystal structure of an
SDE, and a new mechanistic model for nucleophilic SDE
opening supported by computational analysis.
Scheme 1. Proposed mechanistic models for SDE opening.
Despite the mechanistic rationales suggested by others,[5–9]
the structure of the SDE, along with certain other observa-
tions,[11] led us to hypothesize that SDE opening proceeds
such that both epoxides open in a concerted fashion (I,
Scheme 1). This hypothesis is consistent with the mild
reaction conditions under which SDEs react and is reasonable
in terms of stereoelectronics. To test this hypothesis, we
examined a series of related nucleophiles, a key subset of
which is shown in Table 1. Anionic and neutral nucleophiles
have been shown to add to SDEs efficiently under non-acidic
conditions, including deprotonated benzenesulfonamide, lith-
ium benzimidate, azide,[1] certain aliphatic alkoxides, phenyl
thiolate, chloride, fluoride,[5] organocuprates,[2] along with
ammonia and a limited number of secondary amines.[5]
Cyanide, an anionic carbon nucleophile, as well as the anionic
oxygen nucleophiles acetate[12] and phenoxide, added to give
the corresponding products in good yield (Table 1, entries 1–
3). Stoichiometric quantities of water, aliphatic alcohols, and
phenol do not add at useful rates to SDEs under neutral
conditions (for example, entry 4 in Table 1). When used as a
solvent or cosolvent, however, water,[5] methanol, and etha-
Table 1: Allene oxidation and reaction with various nucleophiles.[a]
Entry
Nucleophile
Solvent
t [h]
Yield [%][e]
1[b]
2[b]
3[c]
4[c]
5[c]
6[d]
7[d]
8[d]
nBu4N+CNꢀ
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1
1
4
12
77
nBu4N+OAcꢀ
PhOꢀ
70
65[f,g]
0
PhOH
2-hydroxypyridine
N,N-dimethylacetamide
N-ethylacetamide
2-pyrrolidinone
12
98[g]
0[h]
45 min
45 min
45 min
trace[h]
75[i]
[a] Conditions: 3.0 equiv DMDO (1:1 d.r.). [b] 1.1 equiv nucleophile.
[c] 1 equiv nucleophile. [d] 5 equiv nucleophile. [e] Yield after chroma-
tography based on SDE except where noted. [f] 1 equiv PhOH, 1.1 equiv
K2CO3, 10 mol% [18]crown-6 in THF. [g] Yield after chromatography
based on nucleophile. [h] Determined by 1H NMR of crude reactions.
[i] Product unstable (see the Supporting Information). DMDO=2,2-
dimethyldioxirane.
[*] S. D. Lotesta, S. Kiren, Prof. R. R. Sauers, Prof. L. J. Williams
Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey
Piscataway, NJ 08854 (USA)
nol, but not tert-butanol, were found to add efficiently to
SDEs (data not shown). Surprisingly, one equivalent of 2-
hydroxypyridine added smoothly under neutral conditions to
give the O-alkylated product (Table 1, entry 5).
One explanation for the facile addition of 2-hydroxypyr-
idine invokes the amide tautomer. Consequently, the reac-
tivity of a series of amides was examined under identical
conditions. Although virtually no reaction took place between
SDEs and N,N-dimethyl acetamide or N-ethyl acetamide, the
cis amide 2-pyrrolidinone added rapidly to give the O-
alkylated imidate in good yield (see entries 6–8 in Table 1).
Fax: ( +1)732-445-5312
E-mail: ljw@rutchem.rutgers.edu
[**] Generous financial support from Merck & Co., Johnson & Johnson
(Discovery Award), donors of the American Chemical Society
Petroleum Research Fund, NIH (GM-078145), and Rutgers, The
State University of New Jersey is gratefully acknowledged. We thank
the National Center for Supercomputer Applications for allocation
time on the IBM P Series 690 computer to R.R.S. (Grant CHE30060)
and Dr. Tom Emge for crystallographic analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2 illustrates that benzamide, thiobenzamide, and ben-
zamidine also add to SDEs. This result constitutes a novel
entry to heterocycles from allenes that complements other
methods (for example, the Hantzsch method), as the synthesis
SDE opens sequentially (III!IV,[5] V!VI,[6] VII!VIII;
Scheme 2).[7] A mechanism wherein both epoxides open in
concert could account for the new findings and is consistent
with the earlier data as well (Scheme 1, compare I with II, X =
O, N, S ; Y = N; Z = H).
Table 2: Allene conversion to nitrogen heterocycles via SDEs.[a]
Entry Allene Amide/
amidine
Conditions
t
[h]
Product[b]
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
1a
1a
1b
1b
1a
1a
1a
1b
1b
1b
C6H5CONH2
C6H5CSNH2
C6H5CONH2
C6H5CSNH2
C6H5CONH2
C6H5CSNH2
C6H5CNHNH2
C6H5CONH2
C6H5CSNH2
C6H5CNHNH2
A[c]
A
A
A
B
B
A
B
B
B
24 2a (X=O)
12 2a (X=S)
84 2b (X=O)
17 2b (X=S)
48 3a (X=O)
24 3a (X=S)
60 3a (X=NH) 83
72 3b (X=O)
35 3b (X=S)
74
80
81
76
66
83
Scheme 2. Earlier proposed intermediates for SDE opening.
To further evaluate this proposal, we gathered additional
structural and computational data. Table 3 presents the first
crystal structure of an SDE (4). Key bond lengths are
tabulated and compared with computation. Importantly,
molecular-mechanics-based methods (for example, MM2,
MM3, MM4) do not provide accurate optimization of SDEs.
PM3- or higher-level computations, which incorporate quan-
tum effects, appear necessary for accurate SDE modeling (for
47
60
21 3b (X=NH) 78
[a] Conditions A: DMDO, ꢀ408C, 1 h (1a 1:1 d.r., 1b 3:2 d.r.), 5 equiv
nucleophile, CHCl3, RT; conditions B: DMDO, ꢀ408C, 1 h; 5 equiv
amide, CHCl3, RT, then 10 mol% p-TsOH, reflux. [b] Yield after
chromatography based on SDE. [c] Reaction run in 1:1 CHCl3/THF.
TIPS=triisopropylsilyl.
ꢀ
example, DFT, HF, MP2). The C2 O1/O2 bond lengths of 4
ꢀ
are shorter than those of simple acetals 5. The C2 C1/C3 and
is highly modular and gives carbinol-functionalized azolines
and azoles.[13] Benzamide added very slowly (Table 2,
entries 1 and 3). Nevertheless, even in the presence of
five equivalents of water, a potentially competitive nucleo-
phile, only the oxazoline product was obtained. Thiobenza-
mide (Table 2, entries 2 and 4) and benzamidine (Table 2,
entries 7 and 10) added more rapidly to SDEs than benza-
mide, consistent with the expected increased nucleophilicity
of these reagents. SDE stereochemistry was assigned based on
analogy to earlier models: The first oxidation is highly
selective, the second oxidation is less selective, and the
product ratios matched the SDE ratios.[1–5] Although sponta-
neous formation of imidazoles from the imidazolines compli-
cated imidazoline isolation, thiazolines and oxazolines were
readily obtained in pure form. NOE analysis allowed trans
assignment of the carbinol and the alkyl substutuents of the
azolines (2a and 2b), as expected based on thermodynamic
considerations. In a separate step, dehydration to the
corresponding imidazoles, thiazoles, and oxazoles was readily
achieved. Moreover, oxazoles, imidazoles, and thiazoles were
conveniently prepared in a single flask from the allene
without isolation of intermediates (Table 2, entries 5–10).
The structural dependence and generality of these find-
ings are difficult to reconcile with earlier models of SDE
opening. Previous models suggest that each epoxide of the
Table 3: Key bond lengths [Š] for SDE and proposed transition states.
Structure C1-O1 C2-O1 C2-O2 C3-O2 C2-C1 C2-C3
crystal
4
1.517 1.393 1.393 1.517 1.446 1.446
calculated
4
5
6
7
1.495 1.398
–
–
–
–
–
–
–
–
–
–
–
–
–
1.454
–
1.489
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1.429
1.446
1.490 1.390
8
2.010 1.270 1.750
2.079 1.280 1.607
1.489 1.384 1.397
1.910 1.260 1.960
1.929 1.331 1.439
10
12
13
15
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ꢀ
C2 O1/O2 bond lengths of 4 are shorter than those of
bonded complexes of weak acids, such as methanol, to O2 of
SDE 7 (to give 12) were also identified. Addition of water to
C1 of 12 (to give 14) was found to proceed by way of a lower
enthalpy of activation (19.3 kcalmolꢀ1) than addition to 7
(22.3 kcalmolꢀ1). The alternative pathway, in which water
attacks C3 of 12 (not shown), represents a higher enthalpic
barrier (ca. 1 kcalmolꢀ1).
ꢀ
ꢀ
epoxides 6; however, the C1 O1 and C3 O2 bonds are longer
ꢀ
than the average length of C O bonds of epoxides.
Reaction pathways consistent with models I and II have
been identified by DFT[14] calculations as highly exothermic
transformations wherein both epoxides open in concert. As
shown in Figure 1 and Scheme 3, the reaction paths and
The simultaneous coordination of 2-pyrroli-
dinone to a proximal SDE oxygen atom (O1)
and attack at the proximal carbon atom (C1) is
not geometrically feasible. Nonetheless, a tran-
sition structure for 2-pyrrolidinone-induced
SDE opening was found (7!10!11) and
proved closely related to the other addition
reactions of this study. This transition-state
structure features attack by the carbonyl lone
pair at the proximal carbon atom (C1) and cis
amide hydrogen coordination to the distal
oxygen atom (O2).
Three classes of nucleophiles that add to
SDEs are discernable. First, SDE opening is
readily achieved by anionic carbon, nitrogen,
oxygen, sulfur, and halide nucleophiles. As with
other nucleophilic openings, SDE opening takes
place with inversion at the least-substituted
site.[1,2,5] Second, weakly acidic reagents, for
example, water, methanol, and phenol, open
SDEs very slowly under neutral conditions.
Consequently, a large excess of reagent is
required for reasonable reaction times. This
observation may be reflective of the influence
of mass action, higher-order transition states, hydrogen-bond
activation, or a combination of these effects. Third, there is a
structural requirement for certain nucleophiles to add to
SDEs under neutral conditions. Amides, amidines, and
thioamides add to SDEs to give oxazoles and oxazolines,
imidazoles and imidazolines, and thiazoles and thiazolines,
respectively (Table 2). Evidently, alkylation of these nucleo-
philes is followed by addition of the nitrogen atom to the
carbonyl. The structural requirement appears to be an NH
group cis to the amide carbonyl group, or its analogue
(compare entries 6–8, Table 1).
Figure 1. Calculations of relative enthalpies of activation (in kcalmolꢀ1).[14]
Computational studies reveal strikingly similar transistion
states for the three classes of nucleophile. The angle of
nucleophilic attack (Nu-C1-O1: 1588 (8), 1688 (10), 1618 (13),
1708 (15); Scheme 3) reflects a degree of cationic character at
C1.[15] For all nucleophiles in this study, the C1 O1 bond
Scheme 3. Transition-state structures for SDE opening.
ꢀ
ꢀ
ꢀ
lengthens, the O1 C2 bond shortens, and the C2 O2 bond
lengthens upon nucleophilic attack of the SDE, although the
epoxide opening occurs at different rates (compare 8, 10, 13,
and 15, Table 3). Hydrogen bonding to the SDE oxygen atom
that is destined to become the hydroxy group, by solvent or by
the attacking nucleophile, facilitates SDE opening by stabi-
lizing the transition state. It is noteworthy that this analysis
does not preclude sequential epoxide opening; one may
observe (see above) these pathways computationally and
would expect that these pathways could become relevant in
instances in which the solvent or reagent interacts strongly
with alkoxide. Still, taken together, the analysis supports a
transition-state geometries for nucleophilic addition by water,
amide, and chloride are very similar. Key interatomic
distances of reactants and transition structures are included
for comparison in Table 3. As judged by intrinsic reaction-
coordinate calculations, singly opened SDEs (for example,
IV; Scheme 2) do not represent stable intermediates.
We focused our computational analysis on the addition of
water and related nucleophiles to SDEs (Figure 1 and
Scheme 3). A single transition barrier 8 connects water and
the SDE 7 with the substituted ketone 9. Stable hydrogen-
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Angewandte
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mechanistic framework wherein nucleophilic addition to
SDEs involves concerted, asynchronous opening of both
epoxides.
Anionic reagents are excellent nucleophiles for SDE
opening, although side reactions can be problematic.
Although many neutral reagents are not good nucleophiles,
SDEs can be activated in the presence of hydroxylic
reagents.[3,4] Coordination to the distal SDE oxygen atom
(O2 in 13) lowers the barrier for attack at the proximal SDE
carbon atom (C1 in 13). In this way, hydrogen-bond activa-
tion, and presumably Lewis or Brønsted acid activation in
general, acts cooperatively to relieve ring strain in both
epoxides through SDE opening. The remarkable finding that
amides, amidines, and thioamides give heterocycles upon
addition to SDEs is readily understood: Certain nucleophiles
are able to act simultaneously as hydrogen-bonding activators
and as nucleophiles.
The new mechanistic model presented here is consistent
with all the available data. Nucleophilic SDE opening is
rationalized in terms of a reactivity continuum that involves
the concerted, asynchronous opening of both epoxides. This
process is facilitated by coordination to the oxygen atom
destined to become the hydroxy group.
[11]B. A. Hess, Jr., J. K. Cha, L. J. Schaad, P. L. Polavarapu, J. Org.
Chem. 1992, 57, 6367.
[12]Under these non-acidic conditions, only acetate addition is
observed. In contrast, exposure of an SDE to acetic acid in
CH2Cl2 gives oxetanone, enone, and acetate-addition products;
see: J. K. Crandall, W. H. Machleder, J. Am. Chem. Soc. 1968, 90,
7292; J. K. Crandall, W. W. Conover, J. B. Komin, W. H.
Machleder, J. Org. Chem. 1974, 39, 1723.
[13]a) A. Hantzsch, J. H. Weber, Ber. Dtsch. Chem. Ges. 1887, 20,
3118; b) R. Robinson, J. Chem. Soc. 1909, 95, 2167; c) S. Gabriel,
Ber. Dtsch. Chem. Ges. 1910, 43, 1283; d) M. R. Grimmett in
Advances in Heterocyclic Chemistry, Vol. 27 (Eds.: A. R.
Katritzky, A. J. Boulton), Academic, New York, 1980, pp. 241 –
326; e) J. V. Metzger in Comprehensive Heterocyclic Chemistry,
Vol. 5 (Eds.: A. R. Katritzky, C. W. Rees), Pergamon, New York,
1984, pp. 345 – 498; f) J. V. Metzger in Comprehensive Hetero-
cyclic Chemistry, Vol. 6 (Eds.: A. R. Katritzky, C. W. Rees),
Pergamon, New York, 1984, pp. 235 – 332; g) R. R. Gupta, M.
Kumar, V. Gupta, Heterocyclic Chemistry II: Five-Membered
Heterocycles, Vol. 2, Springer, Berlin, 1999, pp. 374 – 434;
h) Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A,
Vol. 60 (Ed.: D. C. Palmer), Wiley, Hoboken, NJ, 2003.
[14]a) Gaussian03 (RevisionB.02): M. J. Frisch et al., see the
Supporting Information; b) A. D. Becke, J. Chem. Phys. 1993,
98, 1372; c) B. Miehlich, A. Savin, H. Stoll, H. Pruess, Chem.
Phys. Lett. 1989, 157, 200; d) C. Lee, W. Yang, R. G. Parr, Phys.
Rev. B 1988, 37, 785.
Received: April 1, 2007
Published online: August 9, 2007
Keywords: allenes · nitrogen heterocycles · reaction mechanism ·
.
spirodiepoxides
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Chem. Soc. 2004, 126, 15348, and references therein.
[2]P. Ghosh, S. D. Lotesta, L. J. Williams, J. Am. Chem. Soc. 2007,
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[15]This observation is also consistent with observations discussed in
J. K. Crandall, D. J. Batal, F. Lin, T. Reix, G. S. Nadol, R. A. Ng,
Tetrahedron 1992, 48, 1427.
[3]S. D. Lotesta, Y. Hou, L. J. Williams, Org. Lett. 2007, 9, 869.
Angew. Chem. Int. Ed. 2007, 46, 7108 –7111
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