C-H carbene insertion of α-diazo acetamides by photolysis in non-conventional media

Article abstract of DOI:10.1021/jo800980c

(Chemical Equation Presented) Light from a mercury vapor high-pressure lamp was used to induce the photolytic decomposition of α-diazo acetamides in hexane and in nonconventional media such as water or a film. The corresponding a- and/or γ-lactams were ob

Full text of DOI:10.1021/jo800980c

C-H Carbene Insertion of r-Diazo Acetamides by Photolysis in
Non-Conventional Media
Nuno R. Candeias,† Pedro M. P. Gois,†,§ Luis F. Veiros,‡ and Carlos A. M. Afonso*,†
Centro de Qu´ımica-F´ısica Molecular, IN - Institute of Nanosciences and Nanotechnology, and Centro de
Qu´ımica Estrutural, Departamento de Engenharia Qu´ımica e Biolo´gica, Instituto Superior Te´cnico,
1049-001 Lisboa, Portugal, and iMed.UL, Faculdade de Farmácia da UniVersidade de Lisboa,
AV. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
carlosafonso@ist.utl.pt
ReceiVed May 6, 2008
Light from a mercury vapor high-pressure lamp was used to induce the photolytic decomposition of
R-diazo acetamides in hexane and in nonconventional media such as water or a film. The corresponding
ꢀ- and/or γ-lactams were obtained in reasonable yields and in some cases with good diastereoselectivities
with no need to use a metallic catalyst. Experimental studies on chiral substrates demonstrated the
occurrence of insertion with retention of configuration.
SCHEME 1
Introduction
More than a half-century has passed since the discovery of
R-diazo carbonyl compounds as excellent candidates for the
construction of new and interesting molecules. However, in the
last two decades, they gained special notoriety with the uprising
of catalysis due to the ability of some metals to coordinate with
carbenes that can be generated from the decomposition of the
diazo substituent.1–3 In the absence of catalyst, this decomposi-
tion can be induced by thermolysis or photolysis, generating a
highly reactive intermediate species that in most cases affords
a complex mixture of products. Depending on the diazo
compound and the reaction conditions used, the resultant
products can be derived from C-H or X-H insertion, Wolff
rearrangement, ylide formation, cyclopropanation, R,R-substitu-
tion reaction, ꢀ-hydride elimination, or even other cycloaddition
reactions.4
Parker6 observed that photodecomposition of N-[(ethoxycarbo-
nyl)diazoacetyl]piperidine 1 in carbon tetrachloride yielded the
correspondent ꢀ-lactam 2 derived from C-H insertion in the
R-carbon of the piperidine unit (Scheme 1a), while the use of
N-[(ethoxycarbonyl)diazoacetyl]pyrrolidine 3a and N-[(tert-
butylcarbonyl)diazoacetyl]pyrrolidine 3b afforded the cor-
respondent ꢀ-lactone 4a and, respectively, γ-lactone 4b as a
result of C-H insertion in the ester alkyl chain (Scheme 1b).
R-Diazo ester decomposition was also experimentally inves-
tigated in order to obtain the corresponding lactone. However,
due to the lack of proximity between the O-alkyl substituent
The first example of a photolytic-assisted C-H insertion of
R-diazo amides was reported by Corey and Felix5 in the
synthesis of methyl 6-phenylpenicillanate. Later, Lowe and
† Centro de Qu´ımica-F´ısica Molecular.
‡ Centro de Qu´ımica Estrutural.
§ Universidade de Lisboa.
(1) Padwa, A. HelV. Chim. Acta 2005, 88, 1357–1374.
(2) Maas, G. Chem. Soc. ReV. 2004, 33, 183–190.
(3) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc. ReV.
2001, 30, 50–61.
(4) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091–1160.
(5) Corey, E. J.; Felix, A. M. J. Am. Chem. Soc. 1965, 87, 2518–2519.
(6) Lowe, G.; Parker, J. J. Chem. Soc., Chem. Commun. 1971, 577–578.
5926 J. Org. Chem. 2008, 73, 5926–5932
10.1021/jo800980c CCC: $40.75 2008 American Chemical Society
Published on Web 06/26/2008

Photolysis in Non-ConVentional Media
In accordance with the observations of Rando,9,10 Thornton
et al.15 obtained the intermolecular C-H and O-H insertion
products when three examples of R-diazo acetamides (3a, 8,
and 9) were decomposed by photolysis. Through the decom-
SCHEME 2
and the reactive intermediate, intermolecular reactions were seen
to be preferred. For instance, the decomposition of allyl
diazoacetate in cyclohexane leads to the single formation of
allyl cyclohexylacetate,7 and the decomposition of tert-butyl
diazoacetate yields tert-butyl cyclohexylacetate preferentially
and only 9.5% of the desired lactone.8 In contrast, Rando
observed that photolytic decomposition of N,N-diethyldiazo
acetamide 5 in dioxane provided the intramolecular C-H
insertion products ꢀ- and γ-lactams (6, 7) in 57% and 43% yield,
respectively (Scheme 2).9,10 However, the use of protic solvents
such as methanol had led to the formation of Wolff rearrange-
ment and O-H insertion products and, consequently, a con-
siderable decrease in the formation of γ-lactam. At this point,
an analogy was made with the reported prior results on the
photolysis of ethyl diazoacetate in methanol11 in which inter-
molecular C-H insertion products were suppressed in isopropyl
alcohol.12 Due to these observations, it was assumed that the
formation of the two lactams should arise from different
pathways, in which the ꢀ-lactam transition state originates a
greater charge separation. Through these findings, the authors
claimed that C-H insertion would be circumvented as long as
there was water in the aliphatic site vicinity, and the γ-/ꢀ-lactam
ratio in nonpolar solvents should be governed by statistics.
Later, Tomioka et al.13 found that the intramolecular C-H
insertion process in the decomposition of N,N-diethyldiazo
acetamide 5 could proceed through singlet carbene or singlet
excited-state diazo compound. The authors suggested that the
excited singlet state of N,N-diethyldiazo acetamide 5 could give
rise to the ꢀ-lactam and the Wolff rearrangement product directly
or through the dissociation to nitrogen and singlet carbene. This
singlet carbene could subsequently undergo C-H insertion into
the C-H bonds of the methyl group to give the correspondent
γ-lactam 7. Considering two possible conformational isomers
of the diazo acetamide, in which the carbonyl lays cis (Z) or
trans (E) to the diazo substituent, the authors reasonably
assumed that there are equal populations of both forms. Taking
into consideration the reported study on the rotation of internal
carbon-carbon bonds of diazo ketones,14 the Z form of the
singlet excited state of the diazo compound was indicated as
responsible for the formation of the ꢀ-lactam and Wolff
rearrangement product, while the E form was responsible for
the formation of the γ-lactam (via direct “perpendicular”
insertion) and the O-H insertion products (Scheme 2).13 In this
way, the different ꢀ/γ ratios in different solvents were attributed
to the solvent influence on the E/Z ratio populations.
position of these compounds in binary mixtures of solvents (tert-
butyl alcohol/cyclohexane; tert-butyl alcohol/water), a general
preference toward O-H insertion was observed. Through
comparison of 9 with alkyl diazoacetates,16 the authors claimed
that the electronic influence of the carboxamide substituent
increased the yield of the O-H insertion product when
compared with the ester group. This aspect does not seem to
apply to the decomposition of R-diethoxyphosphoryl homo-
logues since in the dirhodium(II) catalytic decomposition of
R-diazo-R-diethoxyphosphoryl acetamides in water a preference
toward intramolecular C-H insertion was observed, while the
intermolecular O-H insertion of the R-diazo-R-diethoxyphos-
phoryl esters was predominant.17
SCHEME 3
Heterocycles bearing a phosphonate substituent, particularly
ꢀ- and γ-lactams, continue to be an interesting class of
compounds, not only because of the mimetic phosphonate
substituent but also because of their ability of being easily
converted to other functional groups through the Horner-
Wadsworth-Emmons reaction.18,19 In the sequence of our work
in synthesizing R-diethoxyphosphoryl-ꢀ- and γ-lactams by C-H
insertion of dirhodium-stabilized carbenes (Scheme 3),20,21 as
in nonconventional media such as ionic liquids22 and water,17,23
we performed a comparable study of a similar transformation
through the photodecomposition of that kind of diazo com-
pounds without the use of a metallic catalyst.
Results and Discussion
Recently, we disclosed the dirhodium(II)-catalyzed intramo-
lecular C-H insertion of diazo acetamides in water.17,23 This
methodology allowed the preparation of lactams in high yields
in aqueous media, in some cases, with high regio- and
(15) Wydila, J.; Thornton, E. R. Tetrahedron Lett. 1983, 24, 233–236.
(16) DoMinh, T.; Strausz, O. P.; Gunning, H. E. J. Am. Chem. Soc. 1969,
91, 1261–1263.
(17) Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M. J. Org. Chem. 2006,
(7) Kirmse, W.; Dietrich, H. Chem. Ber. 1965, 98, 4027–4032.
(8) Kirmse, W.; Dietrich, H.; Bucking, H. W. Tetrahedron Lett. 1967, 1833–
1835.
71, 5489–5497.
(18) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. ReV. 2004, 104, 6177–
6215.
(9) Rando, R. R. J. Am. Chem. Soc. 1970, 92, 6706–6707.
(10) Rando, R. R. J. Am. Chem. Soc. 1972, 94, 1629–1631.
(11) Chaimovich, H.; Vaughan, R. J.; Westheimer, F. H. J. Am. Chem. Soc.
1968, 90, 4088–4093.
(19) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863–927.
(20) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 3798–
3810.
(21) Gois, P. M. P.; Candeias, N. R.; Afonso, C. A. M. J. Mol. Catal. A
(12) Strausz, O. P.; Dominh, T.; Gunning, H. E. J. Am. Chem. Soc. 1968,
90, 1660–1661.
Chem. 2005, 227, 17–24.
(22) Gois, P. M. P.; Afonso, C. A. M. Tetrahedron Lett. 2003, 44, 6571–
(13) Tomioka, H.; Kitagawa, H.; Izawa, Y. J. Org. Chem. 1979, 44, 3072–
3075.
6573.
(23) Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M. Chem. Commun.
2005, 391–393.
(14) Kaplan, F.; Meloy, G. K. J. Am. Chem. Soc. 1966, 88, 950–956.
J. Org. Chem. Vol. 73, No. 15, 2008 5927

Candeias et al.
SCHEME 4
TABLE 1. Photodecomposition of 10a in Different Solvents
TABLE 2. Photodecomposition of 11a in Different Solvents
entry
solvent
reaction time (h)
product/conversiona (%)
1
2
3
4
H2O
24
24
24
24
10c/90b
10c/>97
10c/92
C6H14
i-PrOH
filmc
10c/88b
yielda (%)
a Conversion determined by 31P NMR after solvent removal of the
crude reaction mixture. b Incomplete reaction; the other compound
detected in the mixture was only the unreacted starting material. c Film
formed on the surface of the quartz reaction tube by prior slow
evaporation of dichloromethane solution in a rotaevaporator.
entry
solvent
reaction time (h)
cis
trans
1
2
3
H2O
5
8.5
24
14 (15)
30 (35)
12 (13)
43 (44)
34 (31)
26 (36)
C6H14
filmb
a Isolated yields after purification by flash chromatography; the
observed conversion of the crude reaction mixture (by 31P NMR) is
shown in parentheses. b See footnote c of Table 1.
stereoselectivities. The success of this transformation was shown
to be deeply related to the catalyst structure and, most
importantly, to the diazo substrate hydrophobic nature. It was
rationalized that a correct balance between these two factors
would lead to a more hydrophobic environment around the
carbenoid center reducing the competitive attack by water
molecules.
Generally, the reactivity of metallo-carbenoids generated from
R-diazo acetamides is governed by stereoelectronic effects,
among which the conformation adopted by the metallo-
carbenoid is of pivotal importance to determine the insertion
chemo-, stereo-, and regioselectivities.
Recognizing that the R-diazo acetamide structures contribute
decisively to the final metallo-carbenoid conformation, we
envisioned that combining the hydrophobic effect24–26 evidenced
by some R-diazo acetamides in our previous study, with a strong
conformational bias arising from the substrates structure, would
allow the preparation of lactams in water via photodecompo-
sition of R-diazo acetamides.
We were pleased to observe that submitting the R-diazo
acetamide 10a to irradiation generated from a mercury vapor
high-pressure lamp (150 W) in water resulted in the formation
of lactam 10c in 90% isolated yield (Scheme 4).
Surprisingly the photodecomposition of substrate 10a afforded
the aromatic substitution product 10c with a higher selectivity
than the Rh2(OAc)4-catalyzed cyclization in water in which the
ꢀ-lactam 10b was also formed in 10% yield.17,23
Water is obviously the most desirable solvent for many
economical and environmental reasons. Additionally, in chemi-
cal terms, it is undoubtedly a fascinating liquid because it often
exerts a remarkable influence over the chemical transformations
performed in this media.27–33 Therefore, in order to elucidate
the water effect over the reaction, this transformation was carried
out in different solvent systems (Table 1). As shown in Table
1, the γ-lactam was always the preferred product formed even
when the substrate was irradiated almost in the absence of
solvent (a film of substrate was formed by evaporation of
dichloromethane). This reactivity profile indicates that the
success of this reaction is probably more dependent on the native
diazo substrate conformation than to the hydrophobic effect24–26
exerted by the water over the diazo substrate. Moreover, the
high selectivity toward the γ-lactam formation may be also due
to a preferred aromatic substitution mechanism which results
from the reactive species attack on the electron-rich aromatic
ring followed by aromatization.
Encouraged by those results, several R-diazo acetamides were
submitted to the same reaction conditions. We envisioned that
by introducing a bulky tert-butyl group on the acetamide, the
C-H bond of the less bulky N-substituent would be placed in
closer proximity to the reactive center, resulting in higher yields
and selectivities. Regrettably, the photodecomposition of the
nonsymmetric R-diethoxyphosphoryl acetamide 11a in water
afforded the expected γ-lactam but only in moderate yields and
poor stereoselectivities (Table 2). These results were common
to all solvent systems tested for this substrate. In order to clarify
if the observed low selectivity was due to product decomposi-
tion, a cis/trans mixture of the isolated lactam 11c was irradiated
over 24 h in hexane and only 4% decomposition was observed
together with a change of the diastereoisomeric ratio (from trans/
cis ) 2:1 to trans/cis ) 1.5:1).
In our previous study, it was clear that the phosphoryl group
provided strong affinity for water molecules, moreover, as a
bulky group, it may exert a strong conformational effect over
the reactive conformation. For these reasons, several diazo
acetamides with different R-substituents were studied.
In fact, the R-substituent proved to have a fundamental impact
on the cyclization scenario (Table 3). Maintaining the asymmetry
in the acetamide substituent, the ethoxycarbonyl group favored
the intramolecular C-H process, yielding the corresponding
ꢀ-lactam 12b in 71% isolated yield with a remarkable stereo-
selectivity (entry 1). This yield is close to the one observed in
hexane (entry 2). Considering the solvent free-conditions, the
yield decreased considerably to 56% (entry 3), probably as a
result of competitive reactions. As in the case of 11c, trans
(24) Biscoe, M. R.; Breslow, R. J. Am. Chem. Soc. 2003, 125, 12718–12719.
(25) Breslow, R. Acc. Chem. Res. 1991, 24, 159–164.
(26) Breslow, R. J. Phys. Org. Chem. 2006, 19, 813–822.
(27) Sinou, D. AdV. Synth. Catal. 2002, 344, 221–237.
(28) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209–217.
(29) Li, C. J. Chem. ReV. 2005, 105, 3095–3165.
(30) Li, C. J. Chem. ReV. 1993, 93, 2023–2035.
(31) Lubineau, A.; Auge, J. Top. Curr. Chem. 1999206.
(32) Lubineau, A.; Auge, J.; Queneau, Y. Synthesis 1994, 741–760.
(33) Hailes, H. C. Org. Process Res. DeV. 2007, 11, 114–120.
5928 J. Org. Chem. Vol. 73, No. 15, 2008

Photolysis in Non-ConVentional Media
TABLE 3. Effect of the r-Substituent on the Photodecomposition of r-Diazo N-Benzyl-N-tert-butyl Acetamides
entry
X
substrate
solvent
reaction time (h)
product
yielda (%)
cis/transb
1
2
3
4
5
6
7
CO2Et
CO2Et
CO2Et
PO(OEt)2
PO(OEt)2
PO(OEt)2
CO2Me
12a
12a
12a
13a
13a
13a
14a
H2O
72
24
23
48
24
48
72
12b
12b
12b
13b
13b
13b
14b
71 (>97%)
75 (>97%)
56 (>97%)
48 (66%)
62 (67%)
54 (66%)
only trans
0.1:1
0.2:1
0.7:1
0.5:1
hexane
filmc
H2O
hexane
filmc
H2O
0.5:1
0.1:1
65 (>97%)
a Isolated yield of the trans-lactam after purification by flash chromatography. The observed conversion determined by 31P or 1H NMR is shown in
b
parentheses. Diastereoisomeric ratio determined by the 31P or H NMR of the crude reaction mixture. c See footnote c of Table 1.
1
TABLE 4. Effect of the r-Substituent on the Photodecomposition of r-Diazo-N,N-Diisopropyl Acetamides
yielda (%)
entry
substrate
X
solvent
reaction time (h)
b
c
d
1
2
3
4
5
6
7
15a
15a
15a
16a
16a
16a
17a
CO2Et
CO2Et
CO2Et
PO(OEt)2
PO(OEt)2
PO(OEt)2
COMe
H2O
45
24
48
24
23
23
58
90
>97
37 (38)
63 (65)
39 (62)
Hexane
filmb
H2O
46 (47)c
30 (31) d
(15)
hexane
filmb
20 (27) e
hexane; H2O; filmb
complex mixture
a Isolated yields after purification by flash chromatography (except entries 1-3, quantitative transformation). The observed conversion of the crude
reaction mixture (determined by 31P NMR) is shown in parentheses. b See footnote c of Table 1. c Diastereoisomeric ratio of the crude reaction mixture:
1:0.1. d Diastereoisomeric ratio of the crude reaction mixture: 1:0.3. e Diastereoisomeric ratio of the crude reaction mixture: 1:0.1.
ꢀ-lactam 13b was irradiated in hexane for 24 h, and in this
case, no decomposition or epimerization was observed.
The lower selectivities obtained in the cases where the
phosphoryl group was used as the R-substituent seem to indicate
that the phosphoryl group influence is made through an increased
interaction with water molecules, probably favoring a conforma-
tion which does not place the C-H insertion center close to
the reactive carbon atom. Furthermore, in terms of substrate
solubility in water, 13a was seen to be much less hydrophobic
than 12a.
this substrate in hexane yielded almost exclusively the C-H
insertion product (90%, entry 2), whereas in water the ꢀ-lactam
formation was considerably lower (58%, entry 1), probably due
to the attack of water molecules on a less “protected” carbene
center.
When acetyl was introduced as the R-substituent (17a), a
complex mixture of products was observed, probably due to
the high reactivity of the formed species which can lead to a
myriad of reactions such as Wolff rearrangement (entry 7).34–36
The hydrophobic requirement was put to test with the
cyclization of substrates 18a and 19a (Scheme 5). When the
hydrophilic diazo acetamide 18a was submitted to irradiation,
it afforded exclusively the R-hydroxy acetamide. This selectivity
toward the alcohol formation probably results from a higher
interaction with water. Unlike the previous diazo acetamides,
diazo acetamide 18a is completely soluble in water. Therefore,
the selectivity toward the intramolecular C-H insertion was
improved by simple introduction of more hydrophobic N-
substituents (substrate 19a) which probably generated a more
hydrophobic environment around the reactive center (Scheme
5).
In regard to the ester influence, ethyl ester 12a and methyl
ester 14a did not lead to any difference in selectivity, which is
expected since the stabilization or destabilization of the reactive
species is almost attributed to the carbonyl moiety.
Once the R-substituent effect was clearly highlighted, the
structure of the acetamide moiety was studied. As stated before,
we presumed that a strong conformational bias would be
determinant for the cyclization success. Therefore, three sym-
metrically N,N-disubstituted diazo acetamides were submitted
to irradiation in the same solvent systems as before (Table 4).
As expected, a general decrease on the selectivity toward lactam
formation was observed, in particular when water was used as
solvent. An important piece of evidence, to corroborate the
necessity of a strong conformational bias to achieve a successful
photoinduced cyclization in water, stemmed from the cyclization
of the ethoxycarbonyldiazo acetamide 15a. The cyclization of
(34) Tomioka, H.; Kondo, M.; Izawa, Y. J. Org. Chem. 1981, 46, 1090–
1094.
(35) Popik, V. V. Can. J. Chem. 2005, 83, 1382–1390.
(36) Novoa, J. J.; McDouall, J. J. W.; Robb, M. A. J. Chem. Soc., Faraday
Trans. 2 1987, 83, 1629–1636.
J. Org. Chem. Vol. 73, No. 15, 2008 5929

Candeias et al.
SCHEME 5
the C3 and C4 steric repulsion which should lead to the
formation of C3-C4 anti epimers. The same applies for the
R-diazo acetamide 20a′′ in which lactam 20b′′ should be formed
together with lactam 21b′′. The formation of γ-lactams due to
the insertion on the primary carbon gives us little or no
information about the mechanistic considerations, and so, they
will not be the focus of our discussion.
In fact, the obtained results for the photolytic and dirhodium-
catalyzed C-H insertion in terms of ꢀ-lactam distribution ratio
were quite similar. In the case where enanteomeric pure R-diazo
acetamide 20a′ was used, only the enanteomeric pure ꢀ-lactam
20b′ was observed (Table 5, entries 1 and 2) together with some
C3-C4 syn epimer, and analogously, the decomposition of
enanteomeric pure 20a′′ led to the formation of lactam 20b′′
with minor C3-C4 syn epimer (Table 5, entries 3 and 4).
Interestingly, the catalyzed C-H insertion led to better regeo-
selectivity but worse diastereoselectivity than photolytic C-H
insertion (Table 5, entries 1 vs 2 and 3 vs 4). For determination
of the absolute relative syn/anti configuration of ꢀ-lactam C3
center (phosphoryl group) and C4 centers, a mixture of
diastereoisomers in a 5:1 ratio was analyzed by NOE contacts
of hydrogen at the C3-position and methyl substituent at the
The substrate hydrophobic nature proved to be a key element
of these cyclizations. This effect can be rationalized either by
the direct irradiation of insoluble droplets of diazo compound
or via the formation of molecular hydrophobic micelles in water;
both ways result in water extrusion from the reactive center,37
favoring the intramolecular C-H insertion in detriment of the
alcohol formation.
In order to determine if the C-H insertion was occurring
without the presence of a triplet species, making this reaction a
suitable one to be used by synthetic chemists, enantiomerically
pure R-diazo acetamides 20a′ and 20a′′ and meso-R-diazo
acetamides 21a were synthesized and submitted to the previous
photolytic conditions in hexane. With these experiments, we
appealed to the well-known fact that a triplet species would
lead to a mixture of diastereoisomers.38–40
1
C4-position in bidimensional H NMR experiments with dif-
ferent mixing times (see the Supporting Information).
The observation that the decomposition of meso-R-diazo
acetamide 21a exclusively led to the formation of lactams 21b′
and 21b′′ without the presence of any detectable amount of 20b′
or 20b′′ through chiral HPLC analysis led us to conclude that
the photolytic C-H insertion occurs with absolute retention of
configuration, and hence, the triplet carbene hypothesis is
discarded for this case.42
Conclusion
For comparison with authentic samples, enanteomerically pure
ꢀ-lactams 20b′ and 20b′′ and the racemic mixture (21b′ + 21b′′)
were also prepared through catalytic decomposition of R-diazo
acetamides 20a′ and 20a′′ and meso compound 21a with
Rh2(OAc)4 in 1,2-dichloroethane, which is a well-known method
for the C-H insertion with retention of configuration.41 Thus,
the dirhodium-catalyzed decomposition of enanteomeric pure
R-diazo acetamides 20a′ and 20a′′ should lead to the formation
of ꢀ-lactams 20b′ and 20b′′ (together with the C3-C4 syn
diastereoisomers, not represented for the sake of simplicity),
while the decomposition of R-diazo acetamide 21a should lead
to the racemate formation of ꢀ-lactam 21b′ and 21b′′ (also with
the C3-C4 syn epimers). According to this approach, if the
photolytic decomposition occurs with configuration retention,
the product distribution related with ꢀ-lactams should be similar
to the one obtained for the catalytic Rh2(OAc)4 decomposition.
On other hand, if a triplet carbene intercedes in the C-H
insertion mechanism, the decomposition of R-diazo acetamide
20a′ should lead to the formation of ꢀ-lactam 20b′ together with
lactam 21b′ in a quasi-equimolar ratio, since the C1′ substituent
would probably not contribute to any considerable steric effect
and the product distribution would be exclusively reflexive of
The solubility of R-diazo acetamides in water seems to be
one of the most important properties which affect the C-H
insertion chemoselectivity reaction. In the case where hydro-
phobic substrates are used, the R-diazo substrates tend to
reorganize in order to diminish the interactions with water,
leading to some conformations that can be very close to the
C-H insertion transition states. This aspect seems more
pronounced in the case where the N-substituents of the R-diazo
acetamide have the ability to “protect” the carbene center from
water. On the other hand, the use of soluble substrates usually
leads to the formation of the intermolecular O-H insertion
products in high selectivities and yields. Nevertheless, it was
seen that the photolysis of both types of compounds in water
can generate the respective products in better selectivities than
when rhodium(II) acetate is used in the same solvent.
The occurrence of C-H insertion with retention of config-
uration supports that it does not occur via triplet carbene.
(42) Considering continuing assumption by the organic chemistry community
on the reactivity of diazo substrates via singlet or triplet carbene species, it could
be supposed for this case that it may occur via singlet carbene.47–49 In line with
this assumption, we performed DFT calculations assuming singlet carbene
(derived from 16a) as the reactive species, and the observed modeling reaction
pathways were consistent with the experimental 16b/16c ratio (Table 4).
However, due to recent studies by femtosecond flash photolysis which imply
the formation of excited diazo species on the Wolff rearrangement50 and 1,2-H
shift,51 another open possibility is that the C-H insertion may occur instead via
excited diazo species.
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2002, 124, 11971–11978.
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5930 J. Org. Chem. Vol. 73, No. 15, 2008

Photolysis in Non-ConVentional Media
TABLE 5. Decomposition of r-Diazo Acetamides 20a′, 20a′′, and 21a
yielda (%)
entry
substrate
reaction conditions
reaction time (h)
20b′
20b′′
ndd
21b′
1b′′
γ-lactam
b
1
2
3
4
5
6
20a′
20a′
20a′′
20a′′
21a
Rh2(OAc)4 1 mol%, C2H4Cl2, reflux
hν, hexane, rt
Rh2(OAc)4 1 mol%, C2H4Cl2, reflux
hν, hexane, rt
Rh2(OAc)4 1 mol%, C2H4Cl2, reflux
hν, hexane, rt
1.5
6
1.5
6
1.8
9
56 (71)
35 (58)c
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
20c′, 17 (20)d
20c′′, 17 (19)d
57 (74)b
c
40 (59)
nd
nd
55e (68)f
61e (77)g
21a
nd
a Isolated yields after purification by preparative TLC (entries 1, 3, 5, and 6) or flash chromatography (entries 2,4); in parentheses is presented the
observed conversion of the crude reaction mixture (determined by 31P NMR). b A mixture of epimers was observed in the crude reaction mixture
(C3-C4 anti/syn 1.2:1). c A mixture of epimers was observed in the crude reaction mixture (C3-C4 anti/syn 3:1). d A mixture of epimers was observed
in the crude reaction mixture (3:1). e Obtained as a racemate of 21b′ and 21b′′. f A mixture of epimers was observed in the crude reaction mixture
(C3-C4 anti/syn 1.3:1). g A mixture of epimers was observed in the crude reaction mixture (C3-C4 anti/syn 10:1). nd: not detected through chiral
HPLC analysis.
by TLC), the solvent was removed under reduced pressure and
the reaction mixture purified by flash chromatography when
needed.
General Procedure for the r-Diazo Photolytic Decomposition in
Water. In a quartz tube, a solution of the R-diazo acetamide
(0.103 mmol) in 1.0 mL of water was irradiated with a mercury
lamp under stirring. After disappearance of all starting material
(monitored by TLC), the solvent was removed under reduced
pressure and the reaction mixture purified by flash chromatog-
raphy when needed.
General Procedure for the r-Diazo Photolytic Decomposition in
a Film. A quartz tube containing a solution of the R-diazo
acetamide (0.103 mmol) in 0.3 mL of dichloromethane was
slowly removed under reduced pressure in a rotatory evaporator,
in such a way that a film was created in the quartz tube walls.
The quartz tube was then attached to a mechanical stirrer which
was maintained under slow rotation while the tube was irradiated
with a mercury lamp under stirring. After disappearance of all
starting material (monitored by TLC), the reaction mixture was
completely dried under reduced pressure and purified by flash
chromatography when needed.
Experimental Section
The preparation of the substrates not described here was
already described elsewhere (compounds 11a, 13a, 16a, 18a,
and 19a described in ref 20, 10a in ref 17, 12a and 15a in ref
43, 14a in ref 44, and 17a in ref 23). Lactams 11c (trans), 13b,
16b, and 19c were obtained as characterized in ref 20, lactam
10c as described in ref 17, lactams 12b and 15b as described in
ref 43, and lactam 14b as described in ref 44. R-Hydroxy
acetamides 16d and 18d were described in ref 17. meso-R-Diazo
acetamide 21a was synthesized on the basis of the preparation
of bis[(R,S)-1-phenylethyl]amine as previously reported.45,46 The
structural assignment of all new compounds was made by
bidimensional NMR techniques (COSY and HMQC).
General Procedure for the r-Diazo Photolytic Decomposition in
Hexane. In a quartz tube under an argon atmosphere, a solution
of the R-diazo acetamide (0.103 mmol) in 1.0 mL of hexane
was irradiated with a mercury lamp (Model Hanau TQ150) under
stirring. After disappearance of all starting material (monitored
(45) Reyes, A.; Juaristi, E. Tetrahedron: Asymmetry 2000, 11, 1411–1423.
(46) Overberger, C. G.; Marullo, N. P.; Hiskey, R. G. J. Am. Chem. Soc.
1961, 83, 1374–1378.
Acknowledgment. We thank Fundac¸a˜o para a Cieˆncia e
Tecnologia (POCI 2010) and FEDER (ref. POCI/QUI/60175/
(47) Baer, T. A.; Gutsche, C. D. J. Am. Chem. Soc. 1971, 93, 5180–5186.
(48) Bodor, N.; Dewar, M. J. S.; Wasson, J. S. J. Am. Chem. Soc. 1972, 94,
9095–9102.
(49) Gutsche, C. D.; Bachman, G. L.; Udell, W.; Bauerlei.S, J. Am. Chem.
Soc. 1971, 93, 5172–5180.
(50) Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.
J. Org. Chem. Vol. 73, No. 15, 2008 5931

Candeias et al.
2004, PTDC/QUI/66695/2006, SFRH/BPD/18624/2004 and
SFRH/BD/17163/2004) for financial support.
and HPLC representative chromatograms resulting from the
C-H insertion of 20a′, 20a′′, and 21a. This material is available
free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Picture of the apparatus
used for the R-diazo acetamides decomposition in solvent free
conditions, preparation of new R-diazo compounds, photolytic
decomposition procedures, NMR spectra of the new compounds,
JO800980C
(51) Motschiedler, K.; Gudmundsdottir, A.; Toscano, J. P.; Platz, M.; Garcia-
Garibay, M. A. J. Org. Chem. 1999, 64, 5139–5147.
5932 J. Org. Chem. Vol. 73, No. 15, 2008