Reaction of α-Peroxy Lactones with C, N, P, and S Nucleophiles: Adduct Formation and Nucleophile Oxidation by Nucleophilic Attack at and Biphilic Insertion into the Peroxide Bond

Article abstract of DOI:10.1021/jo962039l

The reactions of the α-peroxy lactones 1 with a variety of carbon, nitrogen, phosphorus, and sulfur nucleophiles yield, on S_N2 attack at the more electrophilic alkoxy oxygen of the peroxide bond, diverse addition and oxygen transfer products, together with the catalytic Grob-type fragmentation. The nature of the nucleophile determines the fate of the open-chain intermediate I. Thus, protic nucleophiles such as primary and secondary amines and thiols lead to the second intermediate I′ through proton shift subsequent to the S_N2 step, while nonprotic amines and sulfides, as well as diazoalkanes, lead to oxidation products or to the cycloadducts 10-15. Trivalent phosphorus nucleophiles such as phosphines and phosphites and diisopropyl sulfoxylate prefer biphilic insertion, as documented by the fact that the nucleophilicity rather than the steric demand of these reagents controls their reactivity. The labile adducts undergo a variety of transformations to the final stable products. For protic nucleophiles, the amine adducts 5 and 6 are sufficiently persistent for isolation, whereas the sulfenic esters formed by thiol addition are further oxidized to the sulfinic esters 7 and 8 or react with excess thiol to the corresponding disulfides. For aprotic nucleophiles, the dipolar intermediates I decompose into acetone and CO₂ with regeneration of the nucleophile (Grob-type fragmentation), as seen for DABCO and pyridine N-oxide, or they extrude the α-lactone to afford the oxygen transfer product. The corresponding ketones, pyridine N-oxide, sulfoxides, and sulfones are obtained by this route from diazoalkanes, pyridine, sulfides and sulfoxides. Additionally, the diazoalkane intermediates I also cyclize to the cycloadducts 10-12. The thermally labile phosphorus adducts 13-15, which were observed by low-temperature NMR spectroscopy, decompose to the α-lactone and the phosphorus oxides. Analogously, diisopropyl sulfite is obtained from the sulfoxylate adduct. As for the fate of the α-lactones (the reduction products of the α-peroxy lactones), the dimethyl derivative either oligomerizes to the oligoester 2a or is trapped by methanol as the α-methoxy acid 4a, while the spiroadamantyl α-lactone decarbonylates to adamantanone.

Full text of DOI:10.1021/jo962039l

J . Org. Chem. 1997, 62, 1623-1629
1623
Rea ction of r-P er oxy La cton es w ith C, N, P , a n d S Nu cleop h iles:
Ad d u ct F or m a tion a n d Nu cleop h ile Oxid a tion by Nu cleop h ilic
Atta ck a t a n d Bip h ilic In ser tion in to th e P er oxid e Bon d
Waldemar Adam and Llu´ıs Blancafort*
Institute of Organic Chemistry, University of Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received October 31, 1996X
The reactions of the R-peroxy lactones 1 with a variety of carbon, nitrogen, phosphorus, and sulfur
nucleophiles yield, on SN2 attack at the more electrophilic alkoxy oxygen of the peroxide bond,
diverse addition and oxygen transfer products, together with the catalytic Grob-type fragmentation.
The nature of the nucleophile determines the fate of the open-chain intermediate I. Thus, protic
nucleophiles such as primary and secondary amines and thiols lead to the second intermediate I′
through proton shift subsequent to the SN2 step, while nonprotic amines and sulfides, as well as
diazoalkanes, lead to oxidation products or to the cycloadducts 10-15. Trivalent phosphorus
nucleophiles such as phosphines and phosphites and diisopropyl sulfoxylate prefer biphilic insertion,
as documented by the fact that the nucleophilicity rather than the steric demand of these reagents
controls their reactivity. The labile adducts undergo a variety of transformations to the final stable
products. For protic nucleophiles, the amine adducts 5 and 6 are sufficiently persistent for isolation,
whereas the sulfenic esters formed by thiol addition are further oxidized to the sulfinic esters 7
and 8 or react with excess thiol to the corresponding disulfides. For aprotic nucleophiles, the dipolar
intermediates I decompose into acetone and CO2 with regeneration of the nucleophile (Grob-type
fragmentation), as seen for DABCO and pyridine N-oxide, or they extrude the R-lactone to afford
the oxygen transfer product. The corresponding ketones, pyridine N-oxide, sulfoxides, and sulfones
are obtained by this route from diazoalkanes, pyridine, sulfides and sulfoxides. Additionally, the
diazoalkane intermediates I also cyclize to the cycloadducts 10-12. The thermally labile phosphorus
adducts 13-15, which were observed by low-temperature NMR spectroscopy, decompose to the
R-lactone and the phosphorus oxides. Analogously, diisopropyl sulfite is obtained from the
sulfoxylate adduct. As for the fate of the R-lactones (the reduction products of the R-peroxy lactones),
the dimethyl derivative either oligomerizes to the oligoester 2a or is trapped by methanol as the
R-methoxy acid 4a , while the spiroadamantyl R-lactone decarbonylates to adamantanone.
In tr od u ction
tablished that the SN2 mechanism operates for these
reactions, in which the nucleophile attacks the peroxide
bond at the sterically exposed oxygen atom to produce
anionic or zwitterionic adducts; the latter transform to
a variety of oxidized products. While these studies have
provided valuable mechanistic information on oxygen
transfer processes, the oxidations with dioxiranes have
become a general and selective preparative method for
the oxyfunctionalization of organic and organometallic
substrates.3
Reactions of the strained cyclic peroxides 1,2-dioxe-
tanes1,2 and dioxiranes3 with nucleophiles have been well
studied during the last decades. Numerous early ex-
amples of such transformations of dioxetanes are their
deoxygenation by phosphines1a,b and sulfides1c-e and their
reduction by thiols.1f More recently we have carried out
extensive mechanistic investigations on the reaction of
3,3-disubstituted 1,2-dioxetanes with
a variety of
heteroatom,2a π2b,c and carbon2d,e nucleophiles. We es-
Most recently we have directed our attention to the
R-peroxy lactones 1, four-membered cyclic peroxyesters
which were made available by us in earlier times. Their
chemical behavior, except its thermal decomposition with
characteristic chemiluminescence,1g had remained largely
unexplored. We have shown that olefins4 react with the
dimethyl R-peroxy lactone (1a ) through an SN2 attack
preferentially at the alkoxy oxygen of the peroxide bond
due to the inherent polarization by the acyl group. The
final oxidized product may derive from epoxidation and/
or adduct formation, which constitute characteristic
reaction modes, respectively, of dioxiranes and 1,2-
dioxetanes. The preferred reaction type proved to be
sensitive to subtle steric and electronic effects of the
attacking nucleophile.
X Abstract published in Advance ACS Abstracts, February 15, 1997.
(1) (a) Bartlett, P. D.; Baumstark, A. L.; Landis, M. E. J . Am. Chem.
Soc. 1973, 95, 6486-6487. (b) Bartlett, P. D.; Baumstark, A. L.; Landis,
M. E.; Lerman, C. L. J . Am. Chem. Soc. 1974, 96, 5267-5268. (c)
Wassermann, H. H.; Saito, I. J . Am. Chem. Soc. 1975, 97, 905-906.
(d) Campbell, B. S.; Denney, D. B.; Denney, D. Z.; Shih, L. J . Am. Chem.
Soc. 1975, 97, 3850-3851. (e) Adam, W.; Hadjiarapoglou, L.; Mosandl,
T.; Saha-Mo¨ller, C. R.; Wild, D. Angew. Chem., Int. Ed. Engl. 1991,
31, 200-201. (f) Adam, W.; Epe, B.; Schiffmann, D.; Vargas, F.;
Wild, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 249-251. (g) Adam,
W.; Heil, M.; Mosandl, T.; Saha-Mo¨ller, C. R. In Organic Peroxides;
Ando, W., E.; J ohn Wiley & Sons Ltd.: Chichester, 1992; pp 221-
254.
(2) (a) Adam, W.; Heil, M. J . Am. Chem. Soc. 1992, 114, 5591-5598.
(b) Adam, W.; Andler, S.; Heil, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 1365-1366. (c) Adam, W.; Andler, S.; Heil, M.; Voerckel, V. J . Org.
Chem. 1992, 57, 2680-2682. (d) Adam, W.; Treiber, A. J . Org. Chem.
1994, 59, 840-844. (e) Adam, W.; Harrer, H. M.; Treiber, A. J . Am.
Chem. Soc. 1994, 116, 7581-7587.
Herein we focus our attention on the reaction of the
R-peroxy lactones 1 with a variety of carbon and het-
eroatom nucleophiles. Primary and secondary amines
(3) (a) Adam, W.; Hadjiarapoglou, L.; Curci, R.; Mello, R. In Organic
Peroxides; Ando, W., E.; J ohn Wiley & Sons Ltd.: Chichester, 1992;
pp 195-220. (b) Adam, W.; Hadjiarapoglou, L.; Mielke, K.; Treiber, A.
Tetrahedron Lett. 1994, 35, 5625-5628. (c) Adam, W.; Briviba, K.;
Duschek, F.; Golsch, D.; Kiefer, W.; Sies, H. J . Chem. Soc., Chem.
Commun. 1995, 1831-1832. (d) Go¨rth, F. C., Master’s Thesis (Di-
plomarbeit), University of Wu¨rzburg, 1996.
(4) (a) Adam, W.; Blancafort, L. J . Am. Chem. Soc. 1996, 118, 4778-
4787. (b) Adam, W.; Blancafort, L. J . Org. Chem. 1996, 61, 8432-8438.
S0022-3263(96)02039-7 CCC: $14.00 © 1997 American Chemical Society

1624 J . Org. Chem., Vol. 62, No. 6, 1997
Adam and Blancafort
Sch em e 1. Rea ction s of r-P er oxy La cton es 1 w ith C, N, P , a n d S Nu cleop h iles (n u m ber s in br a ck ets
in d ica te th e cor r esp on d in g en tr ies in Ta ble 1)
and thiols were chosen as protic nucleophiles, for which
the SN2 adducts were expected to be sufficiently persis-
tent for isolation. For comparison, it was of interest to
examine the reactivity of tertiary amines and sulfides as
nonprotic nucleophiles. For the sulfide nucleophiles,
additionally the question of competitive sulfide versus
sulfoxide oxidation was to be assessed with the mecha-
nistic probe thianthrene 5-oxide.5 Moreover, the pos-
sibility of biphilic insertion was to be investigated with
trivalent phosphorus nucleophiles1a,b and diisopropyl
sulfoxylate1d for the hitherto unknown, sterically hin-
dered spiroadamantyl-substituted R-peroxy lactone 1b,
for which steric effects should be negligible if a biphilic
mechanism applied. Finally, diazoalkanes were chosen
as carbon nucleophiles to determine whether formal
cycloaddition, the predominant reaction mode for 1,2-
dioxetanes,2d or carbon oxidation, the characteristic
process for dioxiranes,3b would prevail. The results are
displayed in the rosette of Scheme 1 and the details of
the product distribution in Table 1. Clearly, we observe
that the primary mechanistic event is SN2 attack on the
peroxide bond of the R-peroxy lactone by most nucleo-
philes, but biphilic insertion takes place for phosphines,
phosphites, and sulfoxylates.
dicyclohexyl urea by low-temperature filtration over
florisil, and recrystallization from pentane afforded the
pure 1b as the first isolated crystalline R-peroxy lactone.
Attempts to obtain an X-ray structure at low temperature
unfortunately failed.
R ea ct ion s of r-P er oxy La ct on e 1a w it h P r ot ic
Am in es. The reactions of R-peroxy lactone 1a with
benzylamine and morpholine (Table 1, entries 1 and 2)
yielded the R-aminoxy acids 5 and 6, which were isolated
and fully characterized. The free acid functionality of
the morpholine adduct 6 is evidenced by IR bands around
1700 cm-1 and 13C NMR shifts around δ 180. The
benzylamine adduct was isolated as its benzylammonium
salt 5, as shown by the presence of two signals for the
benzylic methylene group in the 1H and 13C NMR spectra.
Rea ction s of r-P er oxy La cton e 1a w ith Th iols.
R-Peroxy lactone 1a afforded with benzyl mercaptan and
thiophenol (Table 1, entries 3-6) the R-sulfinoxy acids 7
and 8, which were isolated after treatment with diazo-
methane as the methyl esters 7′ and 8′. Due to the labile
nature of these products (decomposition during silica gel
chromatography), the yields of isolated material were
low. The sulfinic ester group was assigned by its IR
1
bands around 1190 cm-1 and the H NMR shifts of the
adducts 7′ and 8′. Thus, the benzylic protons of 7′ are
diastereotopic due to the chirality of the sulfinic ester
functionality and appear as an AB system (J gem ) 12.8
Hz), while the aromatic protons of 8′ in the meta position
show a low-field shift to δ 7.90 by the sulfinic ester
substituent. Further evidence for the structures of 7′ and
8′ is given by their independent syntheses from the
corresponding sulfinic acid chlorides and methyl R-hy-
droxy isobutyrate (eq 1), which also allowed their com-
plete characterization. Together with the adducts 7 and
Resu lts
Syn th esis of Sp ir o-Ad a m a n tyl r-P er oxy La cton e
(1b). The new spiro-adamantyl R-peroxy lactone (1b)
(Scheme 2) was synthesized from the corresponding
R-hydroperoxy acid, which was obtained by autoxidation
of the lithium dianion of 2-adamantanecarboxylic acid
in THF at -80 °C. Cyclization of the R-hydroperoxy acid
with dicyclohexyl carbodiimide,6 separation of the formed
(5) (a) Adam, W; Haas, W.; Lohray, B. B. J . Am. Chem. Soc. 1991,
113, 6202-6208. (b) Adam, W.; Golsch, D. Chem. Ber. 1994, 127, 1111-
1113.
(6) Adam, W.; Alze´rreca, A.; Liu, J .-C.; Yany, F. J . Am. Chem. Soc.
1977, 99, 5768-5773.

Reaction of R-Peroxy Lactones with Nucleophiles
J . Org. Chem., Vol. 62, No. 6, 1997 1625
Ta ble 1. P r od u ct Stu d ies for th e Rea ction of r-P er oxy La cton es 1 w ith C, N, P a n d S Nu cleop h iles
reaction conditionsb
product distributionc
oxidation reduction
R-peroxy
lactone
entrya
nucleophiled
temp [°C]
timee [h]
mbf [%]
addition
fragn
1
2
3
4
5
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
BzNH2 (3.0)
morpholine (1.0)
BzSH (0.75)
BzSH (2.39)
PhSH (0.63)
-20
-20
-20
-20
-20
-20
-20
20
-50
-20
-20
-20
-20
-20
-20
-20
-20
-50
-20
-20
-20
-20
20
0.05
0.05
0.05
0.05
0.05
0.05
0.5
168
0.05
0.35
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
3
97
96
95 (5)
91 (6)
42 (7)
39 (7)
31 (8)
36 (8)
65 (9)
-
-
-
2
5
6
12
20
15
5
-
92g
96g
88g
97g
70j
2 (RSSR)
6 (RSSR)
6 (RSSR)
10 (RSSR)
-
2a , 3a h,i
2a , 3a h,i
2a , 3a h,i
2a , 3a h,i
-
27 (2a )
-
-
-
54 (2a )
>95 (4a )
25 (2a )
>95 (4a )
78 (2a )
>95 (2a )
-
49 (2a )
10 (4a )
-
77 (2a )
-
6
PhSH (1.80)
7a
7b
8
pyridine (1.0)
pyridine (1.0)
DABCO (1.0)
pyridine N-oxide (1.0)
MeSMe (1.16)
MeSOMe (1.10)
MeSOMe (1.10)m
PhSPh (1.07)
PhSPh (1.10)m
SSO (1.33)o
>95
-
76 (N-oxide)k
-
-
86j
-
86
91
11
3
9
91j
-
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23a
23b
24a
24b
25
26a
26b
27a
27b
28a
28b
69
98
>95
81
>95
94
>95
94
73
10
>95
93
>95
>95
>95
91
>95
>95
>95
>95
>95
>95
>95
>95
-
57 (RSOR)l
95 (RSO2R)
>95 (RSO2R)
53 (RSOR)n
86 (RSOR)
78p
-
-
-
-
22
-
-
-
16
-
iPrOSOiPr (1.10)q
iPrOSOiPr (2.89)q
CH2N2 (ca. 5)r
CH2N2 (ca. 4)s
Ph2CN2 (1.0)
fluorene-CN2 (1.0)
(CH3OOC)2CN2 (4.0)
Ph3P (1.1)
-
95 [ROS(O)OR]
90 [ROS(O)OR]
-
-
94
-
24 (10)
-
-
-
13 (11)
43 (R2CO)
67 (R2CO)
-
40
-
2
24
0.05
24
0.05
24
16 (12)
-
>95
8
-60
20
75 (13a )
h
17 (2a )
>95 (2a )
53 (2a )
96 (2a )
92 (2a )
-
Ph3P (1.1)
-
>95 (R3PO)
68 (R3PO)
95 (R3PO)
>95 (R3PO)
h
>95 (R3PO)
52 (R3PO)
>95 (R3PO)
55 (R3PO)
>95 (R3PO)
-
C5H9O3P (1.0)t
C5H9O3P (1.0)t
(EtO)3P (5.0)
Ph3P (1.2)
-60
20
-60
-60
20
-60
20
-60
20
23 (14a )
-
-
-
-
0.05
0.05
24
2
50 (13b)
50
70
h
50
46
60
Ph3P (1.2)
-
-
C5H9O3P (1.0)t
C5H9O3P (1.0)t
(EtO)3P (3.0)
(EtO)3P (3.0)
6u
24
48 (14b)
-
-
-
0.15v
24
47 (15b)
-
-
-
a
b
For the “b” runs, the reaction mixtures of the “a” runs were allowed to warm up to room temperature for thermal decomposition. In
CDCl3 unless indicated. c In CDCl3 determined by 1H NMR spectroscopy with hexamethyldisiloxane as internal standard, in CH3CCl3
determined gravimetrically; product structure is indicated in brackets. Number of equivalents in brackets. e Conversion >95% unless
d
indicated. f Mass balance relative to R-peroxy lactone 1; includes the yields of addition, oxidation (or reduction), and fragmentation products.
g
i
h
Yield of adducts 7 and 8 accounts for 2 equiv of R-peroxy lactone 1a . Not quantified due to overlap with other product NMR signals.
j
R-Hydroxy acid 3a detected in form of the corresponding methyl ester after treatment with diazomethane. No other products were
k
l
m
n
observed. Also 21% unidentified products. Also 1% dimethyl sulfone was observed. Run in 1:1 CDCl3/CD3OD as solvent. Also 6%
diphenyl sulfone was observed. o Thianthrene 5-oxide. 67% SOSO and 11% SSO2, xSO ) 0.16. Under oxygen-free reaction conditions
p
q
r
(freeze-pump-thaw method), no change in the product distribution was observed. Run in CH3CCl3, yield of volatile oxidation and
s
fragmentation products not determined. Run in 1:1 CH3CCl3/CH3OH, yield of volatile oxidation and fragmentation products not
determined. 4-Methyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane. Conversion 70%. v Conversion 67%.
t
u
Sch em e 2a
its NMR spectral data, but complete characterization was
not possible due to its decomposition to pyridine N-oxide.
Although adduct 9 was the only product observed right
after completion of the reaction, besides pyridine N-oxide
also ca. 21% unidentified products were observed in the
1H NMR spectrum of the crude reaction mixture (cf.
footnote k). With 1,4-diazabicyclo[2.2.2]cyclooctane (DAB-
CO) and pyridine N-oxide (entries 8 and 9), only catalytic
decomposition of R-peroxy lactone 1a into acetone was
observed without consumption of the nucleophile.
(i) 2 LDA, -20 °C, THF; (ii) 3O2, -70 to -90 °C, THF; (iii)
HCl (10%), -80 °C, THF; (iv) DCC, CH2Cl2, -40 °C.
a
Rea ction s of r-P er oxy La cton es 1a a n d 1b w ith
Non p r otic Su lfu r Nu cleop h iles. The oxidation of
sulfides and sulfoxides by R-peroxy lactones 1a and 1b
(Table 1, entries 10-15) yielded as main products the
corresponding sulfoxides and sulfones, i.e. the respective
oxidation products by transfer of a single oxygen atom.
Small amounts of the sulfones were also observed in the
oxidation of sulfides (cf. footnotes l, n). In the oxidation
of sulfides and sulfoxides run in CDCl3 as solvent (entries
10, 11, and 13), oligoester 2a was observed as reduction
product in moderate yields together with unidentified
material. In methanol as cosolvent (entries 12 and 14),
R-methoxy acid 4a , the known methanol trapping product
of the R-lactone, was obtained quantitatively. Further-
more, the reaction of R-peroxy lactone 1a with thian-
8, the disulfides of the thiols were obtained in low yields.
Variation in the ratio between oxidized thiol and R-peroxy
lactone 1a had little influence on the product distribution.
Together with the sulfur products, the oligomeric ester
2a and methyl R-hydroxy isobutyrate were also observed.
The latter derives from the corresponding R-hydroxy acid
3a after reaction of the crude product mixture with
diazomethane.
Rea ction s of r-P er oxy La cton e 1a w ith Non p r otic
Am in es. Pyridine was oxidized by R-peroxy lactone 1a
to its N-oxide through the intermediate 9 (entries 7a and
7b). The R-pyridinoxy acid 9 was identified in situ by

1626 J . Org. Chem., Vol. 62, No. 6, 1997
Adam and Blancafort
Ta ble 2. Ra te Stu d ies of th e Rea ction of
threne 5-oxide (entry 15) afforded the 5,10-dioxide (SOSO)
and the 5,5-dioxide (SSO2) in 67% and 11% yields (cf.
footnote p).
Sp ir oa d a m a n tyl r-P er oxy La cton e 1b w ith P h osp h or u s
Nu cleop h ilesa
entry
nucleophile
solvent
kb
As for the reaction of the diisopropyl disulfoxylate with
the R-peroxy lactones 1 (entries 16 and 17), the corre-
sponding sulfites were obtained by extrusion of one
oxygen atom. In the case of the R-peroxy lactone 1a
(entry 16), deoxygenation led quantitatively to the oli-
goester 2a , while for the spiroadamantyl derivative 1b
(entry 17) only adamantanone was detected as reduction
product. When the latter reaction was directly monitored
1
2
3
4
5
6
Ph3P
Ph3P
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
22 ( 10
26 ( 2
C5H9O3Pc
C5H9O3Pc
none
0.074 ( 0.005
0.124 ( 0.001
(9.7 ( 0.3) × 10-5
none
(9.2 ( 0.2) × 10-5
At 10 ( 0.5 °C. Entries 1-4 are second-order [s-1 M-1] and
entries 5 and 6 first-order [s-1] rate constants. c 4-Methyl-2,6,7-
trioxa-1-phosphabicyclo[2.2.2]octane.
a
b
1
by H NMR spectroscopy at -50 °C, no reaction inter-
mediate was observed as precursor to the final products
adamantanone and diisopropyl sulfoxylate. Moreover, no
changes in the product composition were found when the
reaction was conducted under rigorously deoxygenated
conditions by applying the freeze-pump-thaw method
(Table 1, footnote q).
R ea ct ion s of r-P er oxy La ct on e 1a w it h Dia zo-
m eth a n e Der iva tives. The reaction of R-peroxy lactone
1a with diazomethanes (Table 1, entries 18-22) yielded
the cycloadducts 10-12 together with substantial amounts
of catalytic decarboxylation of the R-peroxy lactone 1a
and oxidation of the diazo compound to the corresponding
ketone. Only with the less nucleophilic mesoxalic ester
derivative occurred no reaction at -20 °C, but at room
temperature thermal decomposition of the R-peroxy lac-
tone 1a took place (entry 22).
For the diphenyl and fluorenyl derivatives, the adducts
11 and 12 were isolated and fully characterized. The 1,3-
dioxolan-4-ones 10-12 showed a typical carbonyl IR band
at 1765 cm-1 and 13C NMR shifts at δ 176. The
diazomethane adduct 10 was identified and quantified
by GC analysis and coinjection with an independently
synthesized sample.7 Since the reactions with diazo-
methane (entries 18 and 19) were run in nondeuterated
solvents, the volatile oxidation product of diazomethane,
namely formaldehyde, was not detected, and the extent
of oxidation was quantified in terms of the oligoester 2a ,
the known reduction product of R-peroxy lactone 1a .8
Fragmentation of R-peroxy lactone 1a into acetone was
also not quantified in these cases, which accounts for the
low mass balance. When the reaction of R-peroxy lactone
1a with diazomethane was carried out in methanol as
cosolvent, the R-methoxy acid 4a was obtained from
R-lactone as trapping product.9
goester 2a . Also in the other cases simultaneous direct
formation of the phosphorus oxidation product was
observed at low temperature. As for the dioxaphosphol-
anones 13-15, the phosphorus coupling constants with
the ring carbon atoms show typical values of 3-13 Hz
for a two-bond interaction, and the 31P NMR shifts are
characteristic for such cycloadducts. Thus, the adducts
14a , 14b, and 15b of the insertion of the corresponding
phosphites into the peroxide bond of R-peroxy lactones
1a and 1b showed resonances between δ 50 and 60,
which are in good agreement with reported values for
analogous pentacovalent phosphorus compounds.1a,b,9a,b
The assignment of the five-membered ring structure is
also unequivocal in the case of the adamantyl derivative
13b, which has a 31P NMR shift of δ 24.9, again in good
accordance with reported values.1a,b In contrast, the
phosphorus shift of the dimethyl adduct 13a occurs at
higher field (δ 9.4). Since negative phosphorus shifts are
reported for the open, betainic form of analogous
dioxaphospolanes,9b the measured value of δ 9.4 is an
indication that adduct 13a equilibrates fast between the
closed five-membered ring and the open zwitterionic
form.
For mechanistic purposes, the rates for the reaction of
the adamantyl R-peroxy lactone 1b with triphenylphos-
phine and the bicyclic phosphite methyltrioxaphosphabi-
cyclooctane were measured in dichloromethane and
acetonitrile9c at 10 °C by using the chemiluminescence
decay method (Table 2). As expected, the results show
a greater reactivity (approximately two orders of mag-
nitude higher) for the triphenylphosphine compared to
the bicyclic phosphite; however, the solvent effect is small
since the rates in acetonitrile are only slightly (twofold)
higher for the bicyclic phosphite (entries 3 and 4) and
within the experimental error for triphenylphosphine
(entries 1 and 2).
While all adducts 13-15 decomposed on standing at
room temperature, they showed different thermal per-
sistence at low temperatures. Thus, the triphenylphos-
phine adducts 13a ,b persisted for a few hours at -20 °C,
while the phosphite adducts 14a ,b and 15b decomposed
slowly at that temperature. In all cases, the total
decomposition of the adducts led quantitatively to the
corresponding phosphine oxides and phosphates. How-
ever, a difference in chemical behavior was found be-
tween the dimethyl adducts 13a and 14a , which also
quantitatively led to the oligoester 2a , and the adamantyl
derivatives 13b, 14b and 15b. Thermal decomposition
of the latter gave substantial amounts of adamantanone
(50-70%) and the corresponding phosphine oxide or
phosphate quantitatively.
Loss due to evaporation of the volatile products 10 and
4a during the workup accounts for the low yield of
isolated products on the preparative scale.
Rea ction s of r-P er oxy La cton es 1a a n d 1b w ith
P h osp h or u s Nu cleop h iles. The reactions of R-peroxy
lactones 1a and 1b with phosphorus nucleophiles (Table
1, entries 23-28) were run in deuterochloroform at -60
1
°C and directly monitored by H NMR spectroscopy at
that temperature to detect possible reaction intermedi-
ates. The corresponding insertion products, namely the
dioxaphospholanones 13-15, were observed in all cases
except in the reaction between R-peroxy lactone 1a and
triethyl phosphite (entry 25). In the latter case, the
quantitative oxidation of the phosphite to the phosphate
was observed with concomittant formation of the oli-
(7) Farines, M.; Soulier. J . Bull. Soc. Chim. Fr. 1970, 1, 332-340.
(8) Chapman, O. L.; Wojtowski, P. W.; Adam, W.; Rodr´ıguez, O.;
Ruckta¨schel, R. J . Am. Chem. Soc. 1972, 94, 1365-1367.
(9) (a) Denney, B. D.; J ones, D. H. J . Am. Chem. Soc. 1969, 91,
5821-5825. (b) Ram´ırez, F. Acc. Chem. Res. 1968, 1, 168-174. (c)
Adam, W.; Ram´ırez, R. J .; Tsai, S.-C. J . Am. Chem. Soc. 1969, 91,
1254-1256.
Discu ssion
Our results of the reaction between R-peroxy lactones
1a and 1b and a set of C, N, P, and S nucleophiles (Table

Reaction of R-Peroxy Lactones with Nucleophiles
J . Org. Chem., Vol. 62, No. 6, 1997 1627
Sch em e 3. Mech a n ism for th e Rea ction of r-P er oxy La cton e 1a w ith C, N, P , a n d S Nu cleop h iles
1) show three formal reaction types: addition of the
nucleophile to the peroxide bond of R-peroxy lactone 1,
which leads either to the open-chain adducts 5-9 or to
the cycloadducts 10-15, oxidation of the nucleophile by
oxygen transfer with concomitant reduction of the R-per-
oxy lactone, and decarboxylation of the latter to the
corresponding ketone by fragmentation. Our reaction
modes are rationalized in Scheme 3 by the open-chain
adducts I and I′, which arise from the attack of the
nucleophile at the more electrophilic alkoxy oxygen of
R-peroxy lactone 1, in analogy to our recent findings for
the reaction of R-peroxy lactone 1a with olefins.4 Ad-
ditionally, direct insertion of the nucleophile into the
peroxide bond to afford cycloadducts is postulated.
In our previous studies on the reaction of the related
3,3-disubstituted 1,2-dioxetanes with a series of nucleo-
philes, which yielded a comparable set of products,2 we
postulated the intermediacy of an adduct from the SN2
attack of the nucleophile on the less hindered oxygen of
the peroxide bond. Furthermore, for the reactions of
sterically hindered tetrasubstituted 1,2-dioxetanes with
trivalent phosphorus,1ab,10 arsenic and antimony11 nu-
cleophiles, as well as di- and trisubstituted 1,2-dioxetanes
with sulfoxylates,1d which lead to the corresponding
heteroatom-substituted dioxolanes, a biphilic insertion
mechanism has been postulated on the basis of kinetic
measurements (Hammett correlations10a and isotopic
effects10b). Biphilic insertion has also been postulated for
monovalent metal complexes.12
isolated for morpholine in form of acid 6 (entry 2), while
the benzylamine adduct reacted further with excess base
to the salt 5 (entry 1), which was isolated (Scheme 3, path
A). The different behavior of the amine adducts derives
from the higher basicity of benzylamine, which is proto-
nated by the acid functionality.
The benzylmercaptan and thiophenol adducts I′ (Table
1, entries 3-6) exhibited two subsequent transforma-
tions, namely oxidation of the sulfenic to the isolated
sulfinic esters 7 and 8 by a second R-peroxy lactone 1a
(Scheme 3, path B) and reaction with a thiol molecule to
the corresponding disulfide (Scheme 3, path C).13 In
parallel, the oligoester 2a , the reduction product of the
R-peroxy lactone 1a , and the R-hydroxy acid 3a , produced
by the SN2 attack on the sulfenate, were observed. No
sulfenic ester was detected even when the reaction was
carried out with an excess of thiol (entries 4 and 6), which
displays the higher reactivity of the sulfenate toward
oxidation in comparison with the thiol. Indeed, oxidation
of sulfenic esters by singlet oxygen14 or mCPBA15 is
known, and it is instructive to compare the present
results with our previous results for the reaction of 3,3-
disubstituted 1,2-dioxetanes with thiophenol.2a In the
(10) (a) Baumstark, A. L.; McCloskey, C. J .; Williams, T. E.;
Chrisope, D. R. J . Org. Chem. 1980, 45, 3593-3597. (b) Baumstark,
A. L.; Vasquez, P. C. J . Org. Chem. 1984, 49, 793-798.
(11) Baumstark, A. L.; Landis, M. E.; Brooks, P. J . J . Org. Chem.
1979, 44, 4251-4253.
(12) Bartlett, P. D.; McKennis, J . S. J . Am. Chem. Soc. 1977, 99,
5334-5336.
In the present study, the SN2 adducts I are formed for
all protic nucleophiles, namely amines (Table 1, entries
1 and 2) and thiols (entries 3-6), as well as for pyridine
(entry 7). Adduct I′ results after nucleophilic attack on
the R-peroxy lactone 1 and subsequent intramolecular
and/or intermolecular protonation. The adduct I′ was
(13) Hogg, D. R. In The Chemistry of Sulphenic Acids and their
Derivatives; Patai, S., Ed.; J ohn Wiley and Sons: Chichester, 1990,
pp 361-402.
(14) Clennan, E. L.; Chen, M.-F. J . Org. Chem. 1995, 60, 6444-
6447.
(15) Pasto, D. J .; Cottard, F. J . Am. Chem. Soc. 1994, 116, 8973-
8977.

1628 J . Org. Chem., Vol. 62, No. 6, 1997
Adam and Blancafort
Sch em e 4. Gr ob-Typ e F r a gm en ta tion s of th e Dip ola r In ter m ed ia tes 16 a n d 17 P r od u ced in th e SN2
Rea ction of P yr id in e N-Oxid es w ith Dim eth yld ioxir a n e a n d r-P er oxy La cton e 1a
latter case the postulated intermediary sulfenic esters
were not further oxidized but reacted with excess thiophe-
nol to give phenyl disulfide. As expected, the more
electrophilic R-peroxy lactone 1a is a stronger oxidant
than 1,2-dioxetanes since it is capable to oxidize the
sulfenic esters in the presence of excess thiol. This is
analogous to the oxidation of thiols to sulfinic acids by
the strong oxidant mCPBA.16
3, path E) in analogy to our findings for 3,3-disubstituted
1,2-dioxetanes and diphenyl sulfide,2a in which a similar
dipolar adduct was detected. Additionally, a nucleophilic
mechanism has been claimed for the reaction of dimethyl
sulfide with benzoyl peroxide.21
For diisopropyl sulfoxylate (Table 1, entries 16 and 17),
which is quantitatively oxidized to diisopropyl sulfite, the
biphilic insertion mechanism (Scheme 3, path G) seems
plausible since this nucleophile reacts readily even with
the sterically severely hindered spiroadamantyl R-peroxy
lactone 1b (entry 17). Thermal decomposition of the
labile sulfurane-type cycloadduct leads to diisopropyl
sulfite and R-lactone (Scheme 3, path H). Indeed, sul-
furane cycloadducts have been observed in the reaction
of sulfoxylates with di- and trisubstituted 1,2-dioxetanes,1d
and a concerted biphilic insertion mechanism has been
postulated for this oxidation. In contrast, biphilic inser-
tion is unlikely for the sulfides since ab initio calculations
(RHF/6-31G**) performed on dimethyl sulfide and dim-
ethyl sulfoxylate as model compounds show that the
LUMO of dimethyl sulfide lies at higher energy than the
one of dimethyl sulfoxylate, the difference is ca. 1.9 eV.
Thus, the back-donation from the peroxide oxygen to the
empty sulfur d orbital is quite probable for the sulfoxylate
but unlikely for the sulfide, whose LUMO lies too high.
For the diazomethane and phosphorus nucleophiles,
the cycloadducts 10-12 (Table 1, entries 18-21) and 13-
15 (entries 23-28) were formed, but an open-chain
intermediate I could not be observed for any of these
nucleophiles even by low-temperature NMR-spectral
monitoring. For the diazomethane derivatives (entries
18-22), two possible mechanisms may be considered,
nucleophilic attack of the carbon atom on the peroxide
bond or carbene formation from the diazoalkane with
subsequent biphilic insertion. Since under the present
reaction conditions (-20 °C), the diazomethane deriva-
tives persist, no carbenes are formed, and the latter
possibility is excluded. Thus, we propose a nucleophilic
end-on attack along the peroxide bond axis in which
steric effects determine the lower reactivity of the
aromatic derivatives. After formation of the intermediate
I, cyclization (Scheme 3, path F) or intramolecular SN2
attack (path E) lead to the corresponding dioxolanones
10-12 or ketones and R-lactone. In contrast to our
previous work on the reaction of diazoalkanes with 1,2-
dioxetanes,2d for which cycloaddition occurred in high
yields, in the present study oxidation of the diazoalkanes
to the ketones is the major pathway. Thus, the oxygen
As for pyridine (entry 7), the type I adduct 9 could be
observed at low temperature and was converted to
pyridine N-oxide as major product (Scheme 3, path E),
in contrast to its known behavior in basic aqueous media,
in which Grob-type fragmentation and ring-opening by
nucleophilic attack of hydroxide ion are observed.17 For
DABCO (entry 8) and pyridine N-oxide (entry 9), no
intermediates or addition products could be detected.
Instead, catalytic decarboxylation of the R-peroxy lactone
1a to acetone was observed. Participation of the inter-
mediate I is plausible in these cases in analogy to what
is known for other peroxides. Thus, for DABCO a
zwitterionic adduct was detected in the reaction with 1,2-
dioxetanes,2a and the reaction with tert-butyl peroxy
esters was also postulated to go through an SN2 mech-
anism.18 As for N-oxides, an adduct was also postulated
as intermediate in the deoxygenation of p-(dimethylami-
no)pyridine N-oxide with dimethyldioxirane to afford
singlet oxygen through the dipolar intermediate 16
(Scheme 4).3c Such a Grob-type fragmentation19 of the
dipolar intermediate 17 produced between the R-peroxy
lactone and pyridine N-oxide (Scheme 4) would lead to
acetone and CO2 with release of the pyridine N-oxide
nucleophile (Scheme 3, path D) and constitute catalytic
decomposition of the R-peroxy lactone.
As for the aprotic sulfur nucleophiles (Table 1, entries
10-15), namely sulfides and sulfoxides, the oxygen
transfer products, i.e. the corresponding sulfoxides and
sulfones were obtained as major products. In the case
of diphenyl sulfide, the primary oxidation product, diphen-
yl sulfoxide, was further oxidized in small amounts to
diphenyl sulfone. Analogous to dimethyldioxirane,20 the
electrophilic character of the R-peroxy lactone 1a as
oxidant is confirmed by the low xSO value of 0.16 in its
reaction with thianthrene 5-oxide (entry 15). We propose
the oxidation pathway through the intermediate I (Scheme
(16) Filby, W. G.; Gu¨nther, K.; Penzhorn, R. D. J . Org. Chem. 1973,
38, 4070-4071.
(17) Sliwa, H.; Tartar, A. J . Heterocycl. Chem. 1977, 14, 631-635.
(18) Srinivas, S.; Taylor, K. G. J . Org. Chem. 1990, 50, 1779-1786.
(19) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535-546.
(20) Adam, W.; Golsch, D.; Go¨rth, F. Chem. Eur. J . 1996, 2, 255-
258.
(21) Pryor, W. A.; Bickley, H. T. J . Org. Chem. 1972, 37, 2885-2886.

Reaction of R-Peroxy Lactones with Nucleophiles
J . Org. Chem., Vol. 62, No. 6, 1997 1629
concurrent processes, namely, biphilic insertion and
nucleophilic substitution, and definitive mechanistic
conclusions are questionable.
A point of mechanistic interest is the fate of the
R-lactone, the expected reduction product of the R-peroxy
lactone 1 after oxygen transfer to the heteroatom nu-
cleophile4 (Scheme 3, path E). In the case of R-peroxy
lactone 1a , the intermediary R-lactone was efficiently
trapped by methanol (entries 12, 14, and 19). In aprotic
solvents we found low yields of the oligoester 2a , the
known oligomerization product of the R-lactone.8 The low
yield compared to the oxidized products we attribute to
side reactions of the intermediary R-lactone or its dipolar
valence isomer with the nucleophiles. Such side reac-
tions are inhibited in methanol due to efficient trapping
of the R-lactone (entries 12 and 14). In contrast, for the
spiroadamantyl R-peroxy lactone 1b, the main reduction
product was adamantanone (entries 17 and 26-28). The
R-lactone produced from the thermal decomposition of the
labile cycloadducts (Scheme 3, path H) prefers to decar-
bonylate instead of oligomerizing due to steric effects.
This behavior is in agreement with the known tendency
of higher substituted R-lactones to yield the correspond-
ing ketones through decarbonylation.22
In conclusion, the products obtained during the reac-
tion of R-peroxy lactones 1 with a variety of heteroatom
and carbon nucleophiles reveal the susceptibility of these
electrophilic, strained cyclic peroxy esters toward SN2
attack, a reactivity which the latter also displayed toward
π nucleophiles.4 Moreover, the R-peroxy lactones 1 show
similar reaction modes than that of the related strained
cyclic dioxiranes and 1,2-dioxetanes, although in their
oxidizing strength they fall between dioxiranes (more
reactive) and 1,2-dioxetanes (less reactive), as witnessed
most effectively in the thiol reaction. The formation of
the amine and thiol adducts 5-9 demonstrates that the
nucleophilic attack occurs at the more electrophilic alkoxy
oxygen atom, in spite of steric effects. Subsequently, the
open-chain SN2 adducts I and I′ react through a variety
of channels, namely addition (Scheme 3, paths A, B, and
G), oxidation of the nucleophiles (path E), and catalytic
Grob-type decarboxylation (path D). Furthermore, triva-
lent phosphorus nucleophiles and sulfoxylates also react
through biphilic insertion (path G), in which the nucleo-
philicity rather than steric factors govern this cycload-
dition.
F igu r e 1. Favorable nP-σ* and nO-dP HOMO/LUMO Inter-
actions in the Transition State for the Biphilic Insertion of
Trivalent Phosphorus Nucleophiles into the Peroxide Bond of
R-Peroxy Lactones 1
transfer propensity of the R-peroxy lactone 1a toward
diazoalkanes resembles the established reaction mode of
dimethyldioxirane.3b
The dioxaphospholanones 13-15 are thermally labile
and decomposed to the corresponding phosphorus oxides
(vide infra) with release of the R-lactone (path H).
Together with the cycloadducts, large amounts of phos-
phorus oxidation products (up to 70%) are formed already
at -60 °C (Table 1, entries 23a-28a), conditions at which
the adducts persist. The observed reactivity pattern of
the trivalent phosphorus nucleophiles speaks for a step-
wise SN2 pathway to afford the phosphorus oxides
through the zwitterionic intermediate (Scheme 3, path
E) and through the additional insertion path G. How-
ever, the formation of the products through an end-on
SN2 attack is in disagreement with the observed reactiv-
ity with the adamantyl derivative 1b, for which a linear
SN2 attack on the alkoxy-substituted oxygen along the
peroxide bond axis is sterically impeded. As displayed
by the measured rate constants (Table 2), the reactivity
is determined by the nucleophilicity of the phosphorus
partner rather than by its steric demand. In fact, the
more nucleophilic but bulkier triphenylphosphine (entries
1 and 2) is about two orders of magnitude more reactive
than the less nucleophilic but sterically less encumbered
bicyclic phosphite (entries 3 and 4), which speaks for a
nonlinear approach of the nucleophile on the peroxide
bond. Similar trends, which have been observed for the
cycloaddition of sterically encumbered tetrasubstituted
1,2-dioxetanes with phosphorus nucleophiles, have been
explained in terms of a concerted insertion on the basis
of isotopic and electronic substituent effects.10a,b Conse-
quently, for our case, we suggest a concerted, biphilic
insertion to afford the cycloadducts 13-15 (path G).
As for the geometry of the attack, while the absence of
steric effects rules out the linear attack, the direct
insertion of the phosphorus lone electron pair directly
into the peroxide bond by a symmetrical, perpendicular
attack must be discarded because of electrostatic repul-
sion between the phosphorus lone pair and the peroxide
σ bond and oxygen lone pairs. As a compromise, we
propose the transition state depicted in Figure 1, which
minimizes the aforementioned effects and allows a
secondary interaction between the empty d orbital of the
phosphorus (dP) and the oxygen lone pair (nO) which
ultimately leads to the cycloaddition. A comparison
between the reaction rates in dichloromethane and
acetonitrile (Table 2) shows only a nominal solvent
polarity effect, which in principle supports the proposed
concerted insertion process.9c However, the solvent effect
is a composite one on the total reaction rate of two
Ack n ow led gm en t . We thank the Deutsche For-
schungsgemeinschaft (Schwerpunktprogramm “Peroxid-
chemie: mechanistische und pra¨parative Aspekte des
Sauerstofftransfers”) for generous financial support.
L.B. thanks the Deutscher Akademischer Austausch-
dienst for a doctoral fellowship (1992-1996). The
diligent assistance of Corinna Bachmann (Fall 1993)
and J oachim Telser (Spring 1994) as undergraduate
research participants is much appreciated.
Su p p or tin g In for m a tion Ava ila ble: The Experimental
Section includes the synthesis and complete characterization
of the products (7 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O962039L
(22) Adam, W.; Ruckta¨schel, R. J . Org. Chem. 1978, 43, 3886-3890.