Rh(II)-catalyzed intramolecular C-H insertion of diazo substrates in water: Scope and limitations

Article abstract of DOI:10.1021/jo060397a

Preferential Rh(II) carbenoid intramolecular C-H versus O-H insertion derived from α-diazo-acetamides can be achieved in water by using an appropriate combination of the catalyst and amide groups, which creates a larger hydrophobic environment around the

Full text of DOI:10.1021/jo060397a

Rh(II)-Catalyzed Intramolecular C-H Insertion of Diazo Substrates
in Water: Scope and Limitations
Nuno R. Candeias,† Pedro M. P. Gois,‡ and Carlos A. M. Afonso*,†
CQFM, Departamento de Engenharia Qu´ımica, IST, 1049-001 Lisboa, Portugal, and
REQUIMTE, Departamento de Qu´ımica, FCT-UNL, 2829-516 Caparica, Portugal
carlosafonso@ist.utl.pt
ReceiVed February 24, 2006
Preferential Rh(II) carbenoid intramolecular C-H versus O-H insertion derived from R-diazo-acetamides
can be achieved in water by using an appropriate combination of the catalyst and amide groups, which
creates a larger hydrophobic environment around the reactive carbenoid center.
Introduction
carboxyl group, but also because it allows a simple additional
functionalization in the R-position by a reaction with aldehydes
(Horner-Wadsworth-Emmons reaction).5 In the past few years,
we observed that R-phosphono-R-diazo-acetamides are feasible
candidates for the synthesis of a considerable range of â- and
γ-lactams via Rh2(OAc)4-catalyzed C-H insertion.4 The ob-
served regio and stereoselectivity using Rh2(OAc)4 and the lower
enantioselectivity for several types of Rh(II) chiral catalysts,
demonstrated that the R-phosphoryl group originates a Rh(II)
carbenoid with a reactivity profile quite different from the acetyl,
sulfonyl, or carboxyl groups.1a,4 During those studies, we
observed that the C-H insertion was not affected by the use of
nonanhydrous 1,2-dichloroethane or wet ionic liquids.4c Hence,
these observations prompted us to test the transformation in
water.4d
Dirhodium(II) carbenoids generated from diazo compounds
are powerful reactive intermediates in nonasymmetric and
asymmetric C-C and C-H insertions (intramolecular and
intermolecular), being widely used in the synthesis of a diverse
range of valuable substrates.1 The intramolecular C-H insertion
of Rh(II) carbenoids derived from R-diazo-ketones, esters, and
amides occurs preferentially on the carbon atom in the γ- and
δ-positions to the carbenoid carbon center, yielding the corre-
sponding four- and five-membered ring compounds.1-3 The
regio, stereo, and asymmetric selectivities are strongly dependent
on a combination of factors such as the Rh catalyst, the substrate
structure, the C-H bond nature, and the functional group in
the R-position.3a,4a,b
R-Phosphono-â- and γ-lactams are molecules of considerable
interest, not only because the phosphoryl group mimics the
Water is certainly the cheapest and most environmentally
friendly solvent available.6,7 Apart from this, water has also been
† CQFM, Departamento de Engenharia Qu´ımica.
(4) (a) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 3798-
3810. (b) Gois, P. M. P.; Candeias, N. R.; Afonso, C. A. M. J. Mol. Catal.
A: Chem. 2005, 227, 17-24. (c) Gois, P. M. P.; Afonso, C. A. M.
Tetrahedron Lett. 2003, 44, 6571-6573. (d) Candeias, N. R.; Gois, P. M.
P.; Afonso, C. A. M. Chem. Commun. 2005, 391-393.
‡ REQUIMTE, Departamento de Qu´ımica.
(1) (a) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2004, 3773-
3788. (b) Davies, H. M. L.; Loe, O. Synthesis 2004, 2595-2608. (c) Davies,
H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861-2903. (d) Merlic,
C. A.; Zechman, A. L. Synthesis 2003, 1137-1156. (e) Doyle, M. P.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds; Wiley-Interscience: New York, 1998. (f) Doyle,
M. P. Chem. ReV. 1986, 86, 919-939. (g) Godula, K.; Sames, D. Science
2006, 312, 67-72.
(2) (a) Yoon, C. H.; Zaworotko, M. J.; Moulton, B.; Jung, K. W. Org.
Lett. 2001, 3, 3539-3542. (b) Wee, A. G. H.; Duncan, S. C. Tetrahedron
Lett. 2002, 43, 6173-6176.
(3) (a) Yoshikai, N.; Nakamura, E. AdV. Synth. Catal. 2003, 345, 1159-
1171. (b) Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc.
2002, 124, 7181-7192.
(5) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. ReV. 2004, 104,
6177-6215.
(6) (a) Clifford, A. A. In Green Separation Processes: Fundamentals
and Applications, 1st ed.; Afonso, C. A. M., Crespo, J. P. S. G., Eds.; Wiley-
VCH: Weinheim, Germany, 2005; pp 323-339. (b) Akiya, N.; Savage, P.
E. Chem. ReV. 2002, 102, 2725-2750.
(7) (a) Li, C.-J.; Chen, L. Chem. Soc. ReV. 2006, 35, 68-82. (b) Li, C.
Chem. ReV. 2005, 105, 3095-3165. (c) Lindstrom, U. M. Chem. ReV. 2002,
102, 2751-2771. (d) Lubineau, A.; Auge, J.; Queneau, Y. Synthesis 1994,
741-760. (e) Lubineau, A.; Auge, J. In Modern Solvents In Organic
Synthesis. Top. Curr. Chem. 1999, 206, 1-39.
10.1021/jo060397a CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/22/2006
J. Org. Chem. 2006, 71, 5489-5497
5489

Candeias et al.
FIGURE 1. Solvent dependence of the observed conversion of diazo substrate 1a to â-lactam 2a: 1a (0.075 mmol), Rh2(OAc)4 (1.0 mol %),
solvent (0.5 mL; CDCl3, wet CDCl3, THF, THF/water (1:1), and water); conversion determined by 31P NMR (δ 1a ) 14.70 ppm; δ 2a ) 19.34
ppm).
SCHEME 1a
a Observed conversion by 31P NMR of the crude mixture.
reported as a very useful solvent for highly polar catalyst reuse
under homogeneous conditions by simple product recovery,
using nonpolar solvent extraction or membrane technology.7e,8
Despite the nucleophilic character of the oxygen atom, the
reactivity of the O-H bond, and the high polarity, water can
still be used as solvent in a specific number of synthetic
transformations.6,7 The preferential intramolecular cyclopropa-
nation on styrene and the C-H insertion on triptophan residues
of myoglobin by R-diazo-acetates catalyzed by Rh(II) in aqueous
media have been recently reported.9 These observations are in
clear contrast to the well-assumed reactivity of Rh(II) car-
benoides, where preferential X-H insertion occurs for labile
bonds such as water, alcohols, amines, or thiols.10 This
preferential reactivity has also been efficiently applied for several
synthetic transformations.11 As a result of the present ongoing
interest to enhance the portfolio of synthetic transformations in
water and following our preliminary studies,4d we performed a
systematic study to extend the scope of Rh(II)-catalyzed C-H
insertion of diazo substrates in net water, essentially by studying
the selectivity of C-H and C-H versus O-H insertions.
Discussion
When the substrate model 1a was heated in water at 80 °C
for a long period of time (70 h), only the corresponding alcohol
4a was detected by 31P NMR.4d This product may be the result
of O-H insertion of the formed carbene or the result of a
stepwise mechanism.12 On the contrary, in the presence of Rh2-
(OAc)4 at the same temperature (80 °C) for 24 h, complete
conversion to â-lactam 2a was observed. This was due to the
exclusive reaction of the Rh(II) carbenoid via a C-H insertion
pathway instead of the expected O-H insertion (Scheme 1).4d
Monitoring the conversion of diazo substrate 1a to â-lactam
2a at room temperature by 31P NMR under different solvent
conditions (CDCl3, wet CDCl3, THF, THF/water (1:1), and
water), we observed that water had a remarkable effect on the
reaction rate (Figure 1). The catalyst and the substrate 1a were
incompletely solubilized at room temperature in CDCl3 and
water, respectively; this fact may eventually limit the reaction
rate. In the absence of water, almost no reaction occurs in THF.
In contrast, for THF/water, CDCl3, or water, the reaction
presents similar behavior. Interestingly, the fastest reaction
occurs for wet CDCl3.
(8) Vankelecom, I. F. J. Chem. ReV. 2002, 102, 3779-3810.
Assuming that the rate determining step is the Rh(II)
carbenoid formation13 and according to the proposed mecha-
nism,3 the first step should involve the removal of the labile
axial ligand (if present)14 on the Rh2(OAc)4 catalyst and
nucleophilic attack of the diazo group, followed by N2 extrusion.
The very limited reaction in anhydrous THF is probably due to
(9) (a) Wurz, R. P.; Charette, A. B. Org. Lett. 2002, 4, 4531-4533. (b)
Antos, J. M.; Francis, M. B. J. Am. Chem. Soc. 2004, 126, 10256-10257.
(10) Miller, D. J.; Moody, C. J. Tetrahedron 1995, 51, 10811-10843.
(11) (a) Doyle, M. P.; Yan, M. Tetrahedron Lett. 2002, 43, 5929-5931.
(b) Padwa, A.; Sa, M. M. J. Braz. Chem. Soc. 1999, 10, 231-236. (c)
Moody, C. J.; Miller, D. J. Tetrahedron 1998, 54, 2257-2268. (d) Lu, C.
D.; Liu, H.; Chen, Z. Y.; Hu, W. H.; Mi, A. Q. Org. Lett. 2005, 7, 83-86.
(e) Qu, Z. H.; Shi, W. F.; Wang, J. B. J. Org. Chem. 2004, 69, 217-219.
(f) Livant, P.; Jie, Y. P.; Wang, X. Tetrahedron Lett. 2005, 46, 2113-2116.
(g) Muthusamy, S.; Srinivasan, P. Tetrahedron Lett. 2005, 46, 1063-1066.
(h) Lee, S. H.; Yoshida, K.; Matsushita, H.; Clapham, B.; Koch, G.;
Zimmermann, J.; Janda, K. D. J. Org. Chem. 2004, 69, 8829-8835. (i)
Matsushita, H.; Lee, S. H.; Yoshida, K.; Clapham, B.; Koch, G.; Zimmer-
mann, J.; Janda, K. D. Org. Lett. 2004, 6, 4627-4629. (j) Davies, J. R.;
Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967-3977.
(12) (a) Lu, C.-D.; Liu, H.; Chen, Z.-Y.; Hu, W.-H.; Mi, A.-Q. Org.
Lett. 2005, 7, 83-86. (b) Qu, Z.; Shi, W.; Wang, J. J. Org. Chem. 2004,
69, 217-219.
(13) (a) Pirrung, M. C.; Morehead, A. T. J. Am. Chem. Soc. 1996, 118,
8162-8163. (b) Pirrung, M. C.; Liu, H.; Morehead, A. T. J. Am. Chem.
Soc. 2002, 124, 1014-1023.
5490 J. Org. Chem., Vol. 71, No. 15, 2006

C-H Insertion of Diazo Substrates in Water
TABLE 1. Rh2(OAc)4-Catalyzed Insertion of r-Diazo-acetamides
1b-h in Water
SCHEME 2
the formation of a more stable Rh2(OAc)4 complex as a result
of THF complexation in the axial positions. In water and in
other wet solvents tested, water molecules probably occupy those
positions,14a and the catalyst becomes more reactive due either
to a more labile Rh-ligand bond or to the increased stabilization
of the intermediate that results from the diazo attack on one of
the Rh catalyst atoms (Scheme 2).
These observations prompted us to test the transformation
for a range of substrates in net water. Apart from the phosphoryl
group, the scope of the reaction was studied for different
substituents in the R-position of 1, such as sulfonyl, acetyl, and
ethoxycarbonyl (Table 1, entries 1-4). For all of these substrates
1b-d4d,15 and 1e,15b only C-H insertion was observed, yielding
the corresponding â-lactams 2b-e in high yields. The cycliza-
tion of R-diazo-R-phosphoryl-acetamides 1f-h originated the
expected â- and γ-lactams with similar regioselectivities for the
C-H insertion as the ones previously reported in 1,2-
dichloroethane.4a-c
Despite the success achieved in the cyclization of R-diazo-
R-phosphoryl-acetamides, the decomposition of R-diazo-R-
phosphoryl-acetates in water yielded exclusively the corre-
sponding alcohol 4i instead of the lactone, a product that would
have resulted from a more favorable intramolecular C-H
insertion (Scheme 3).
To explore the solvent influence on the insertion chemiose-
lectivity, a series of reactions were carried out. The cyclization
of 1j in different reaction media achieved a higher selectivity
toward the γ-lactam formation when water was used as the
solvent. This effect was even more pronounced when a saturated
solution of water/NaCl was used (Table 2, entries 1-5).
Taking into consideration the reported findings, we presume
that water stabilizes the intermediate that leads to the γ-lactam
formation via aromatic substitution, which occurs without
competitive O-H insertion (Table 2). The aromatic substitution
is thought to proceed via an electrophilic attack of the metalo-
carbenoid carbon atom on the aromatic ring followed by a 1,2-
hydride shift with a concomitant dissociation of the catalyst and
subsequent aromatization, rather than via a direct C-H inser-
tion.16 This explanation is corroborated by the exclusive
formation of the γ-lactam when the R-diazo-acetamide 1j
reacted with Rh2(pfb)4, this catalyst has more electron-
withdrawing ligands than their counterparts Rh2(OAc)4 and Rh2-
a Isolated yields after purification by flash chromatography; in parentheses
is presented the observed conversion of the crude reaction mixture (by 1H
NMR). b The crude reaction mixture contains the trans and cis isomers (1.3:
1). c Isolated as a mixture of trans and cis isomers (6:1). d Isolated as a
mixture of 2g/3g (1:10).
SCHEME 3 a
(14) (a) Bernal, I.; Bear, J. L. J. Chem. Crystallogr. 2002, 32, 485-
488. (b) Deubel, D. V. Organometallics 2002, 21, 4303-4305. (c) Wynne,
D. C.; Olmstead, M. M.; Jessop, P. G. J. Am. Chem. Soc. 2000, 122, 7638-
7647.
(15) (a) Yoon, C. H.; Zaworotko, M. J.; Moulton, B.; Jung, K. W. Org.
Lett. 2001, 3, 3539-3542. (b) Choi, M. K. W.; Yu, W. Y.; Che, C. M.
Org. Lett. 2005, 7, 1081-1084.
a Observed conversion by 31P NMR of the crude mixture.
(Ooct)4 and, for this reason, generates a more electrophilic
metalo-carbenoid more prone to undergo aromatic substitution
either in C2H4Cl2 or in water (Table 2, entries 7 and 8).17
J. Org. Chem, Vol. 71, No. 15, 2006 5491

Candeias et al.
TABLE 3. Catalyst Effect on the Insertion of 1k in Water
TABLE 2. Regioselectivity Dependence of r-Diazo-acetamide 1j
with Rh(II) Catalyst and Solvent
entry
time (h)
catalyst
yielda (%)
4k/3kb
1
2
3
48
24
24
Rh2(OAc)4
Rh2(pfb)4
Rh2(Ooct)4
71
73
62
only 4k
1:0.85
1:0.46
time
(h)
yielda
(%)
entry
solvent
catalyst
2j/3jb
1
2
3
4
5
6
7
8
C2H4Cl2
C6H6
perfluorodecalin
water
water, NaCl (20% w/w)
water
C2H4Cl2
24
24
24
26
24
48
6
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(Ooct)4
Rh2(pfb)4
50
88
79
97
87
92
97
97
1:4.8
1:5.7
1:7.2
1:10
a Isolated yield as a mixture of 4k and 3k after purification by flash
chromatography. b Observed selectivity of the crude reaction mixture (by
31P NMR).
1:24
1:6.3
only 3j
only 3j
TABLE 4. Catalyst Effect on the Insertion of 1l in Water
water
48
Rh2(pfb)4
a Isolated yield as a mixture of 2j and 3j after purification by flash
chromatography. b Observed conversion of the crude reaction mixture (by
31P NMR).
yield (%) of 2l
Therefore, the increasing selectivity toward the γ-lactam forma-
tion obtained using solvents with higher polarities may be a
result of solvent stabilization of the zwitterionic intermediate
on the aromatic substitution (Table 2, entries 1-5).
entry
catalyst
yielda (%) of 4l
(trans/cis)a
1
2
3
Rh2(OAc)4
Rh2(pfb)4
Rh2(Ooct)4
25 (26)b
c
c
57 (4.5:1)
84 (0.6:1)
97 (1.3:1)
a See footnote (a) in Table 1. b Reaction less clean; other minor
unidentified peaks (14%) were observed by 31P NMR. c None of the alcohol
4l was detected by 31P NMR of the crude reaction mixture.
During this study, the observation was made that substrates
with higher solubility in water, namely the R-diazo-R-phos-
phoryl-acetates (Scheme 3), yielded considerably more alcohol
than those substrates that formed droplets of bulk diazo in the
aqueous phase, typically the diazo-acetamides tested (Table 1).
Exploring this hydrophobic effect,18,19 we anticipated that more
hydrophilic N-substituents would increase the intermediate
interaction with water and, therefore, would lead to a higher
yield of alcohol. As expected, when R-diazo-acetamide 1k was
submitted to Rh2(OAc)4-catalyzed cyclization, the corresponding
alcohol 4k was preferentially obtained (Table 3, entry 1).
Apart from the substrate hydrophobic nature, the catalyst may
also influence dramatically the intermediate reactivity. When
more hydrophobic catalysts such as the rhodium(II) heptafluo-
robutyrate dimer (Rh2(pfb)4) and the rhodium(II) octanoate
dimer (Rh2(Ooct)4) were used in the cyclization of 1k, an
increase was observed in the intermediate hydrophobic nature,
and for this reason, the formation of the γ-lactam was ac-
complished in 34 and 29% conversion, respectively (Table 3,
entries 2 and 3). The same effect was observed in the cyclization
of substrate 1j (Table 2, entry 6). The catalyst influence was
further explored in the cyclization of substrates, which yielded
mixtures of alcohols and lactams in the standard cyclization
with Rh2(OAc)4. In line with the observations for the cyclization
of substrate 1k, we envisioned that an increment on the
hydrophobic nature of the reactive carbene by the catalyst would
prevent the presence of water nearby the reactive metalo-
carbenoid, avoiding in this way the alcohol formation. In fact,
a dramatic change in the reaction selectivity was observed when
more hydrophobic catalysts were tested, particularly the Rh2-
(Ooct)4, which completely suppressed the alcohol formation,
yielding 97% of the â-lactam 2l (Table 4, entry 3). In this
particular substrate in which the N-substituent is the bulky tert-
butyl group, the deprotection of the nitrogen moiety was
observed. This occurred during the reaction and not as a
consequence of the purification procedure.
As in the previous case, the reaction of R-diazo-acetamide
1m yielded a mixture of alcohol 4m and γ-lactam 3m when
the reaction was carried out in the presence of Rh2(OAc)4. In
the same way, a remarkable selectivity was achieved when Rh2-
(Ooct)4 was used, yielding the desired γ-lactam 3m in a 76%
yield (Table 5). Despite the catalyst used, the reaction occurred
in water with high regioselectivity. Only the γ-lactam 3m was
detected in all the crude mixtures, without â-lactam formation.
Similiar to the formation of 4l, the alcohol 4m lost the tert-
butyl group during the reaction.
(16) (a) Tsutsui, H.; Yamaguchi, Y.; Kitagaki, S.; Nakamura, S.; Anada,
M.; Hashimoto, S. Tetrahedron: Asymmetry 2003, 14, 817-821. (b)
Watanabe, N.; Ohtake, Y.; Hashimoto, S.; Shiro, M.; Ikegami, S. Tetra-
hedron Lett. 1995, 36, 1491-1494. (c) Padwa, A.; Austin, D. J.; Price, A.
T.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N.; Winchester, W.
R.; Tran, A. J. Am. Chem. Soc. 1993, 115, 8669-8680. (d) Doyle, M. P.;
Shanklin, M. S.; Pho, H. Q.; Mahapatro, S. N. J. Org. Chem. 1988, 53,
1017-1022. (e) Cox, G. G.; Moody, C. J.; Austin, D. J.; Padwa, A.
Tetrahedron 1993, 49, 5109-5126.
(17) (a) Moody, C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.;
Richards, I. C. Tetrahedron 1998, 54, 9689-9700. (b) Miah, S.; Slawin,
A. M. Z.; Moddy, C. J.; Sheenan, S. M.; Marino, J. P., Jr.; Semones, M.
A.; Padwa, A. Tetrahedron 1996, 52, 2489-2514. (c) Brown, D. S.; Elliot,
M. C.; Moody, C. J.; Mowlem, T. M.; Marino, J. P., Jr.; Padwa, A. J. Org.
Chem. 1994, 59, 2447-2455.
(18) (a) Breslow, R. Acc. Chem. Res. 2004, 37, 471-479; Acc. Chem.
Res. 1991, 24, 159-164. (b) Biscoe, M. R.; Breslow, R. J. Am. Chem. Soc.
2003, 125, 12718-12719. (c) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin,
V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44,
3275-3279.
(19) Manabe, K.; Limura, S.; Sun, X.-M.; Kobayashi, S. J. Am. Chem.
Soc. 2002, 124, 11971-11978.
Interestingly, when the diazo acetamide 1m was submitted
to prolonged heating in the absence of catalyst, the expected
alcohol was not formed. The stability of this diazo compound
contrasts with the reported reaction of diazo 1a in similar
conditions, which yielded exclusively the alcohol 4a (Scheme
1).
Finally, the substrate 1n was designed to contain diverse
N-substituents in their hydrophobic nature. The rationale behind
the choice of this molecule was the observed preference for the
formation of products that resulted from the insertion in the
5492 J. Org. Chem., Vol. 71, No. 15, 2006

C-H Insertion of Diazo Substrates in Water
TABLE 5. Catalyst Effect on the Insertion of 1m in Water
TABLE 7. Reuse of the Rh2(OAc)4 Catalyst Using the Substrate
Model 1aa
entry
time (h)
catalyst
yielda (%)
4m/3mb
1
2
3
4
48
48
24
24
no catalyst
Rh2(OAc)4
Rh2(pfb)4
c
run
yield (%)
Rh in Et2O (%)
86
64
76d
2.4:1
1-9
10
11
88b
90
1.6c
1.1
0.2
0.1:1
Rh2(Ooct)4
only 3md
(63)d
a Isolated yield as a mixture of 4m and 3m after purification by flash
chromatography. b Observed selectivity of the crude reaction mixture (by
31P NMR). c No decomposition of 1m was observed from the crude reaction
(by 31P NMR). d None of 4m was detected by 31P NMR of the crude reaction
mixture.
a For detailed results, see ref 4d. b Average value of isolated yields of
2a. c Average value of percentages of rhodium relative to the initial amount
detected by ICP in the organic phase. d Observed conversion by 31P NMR.
TABLE 8. Reuse of the Rh2(OAc)4 Catalyst Using the Substrate
1ea
TABLE 6. Catalyst Effect on the Insertion of 1n in Water
runa
1
2
3
4
5
entry
solvent
catalyst
time (h)
yielda (%)
4n/3n/3n′b
yieldb (%)
93
105
98
87
(20)c
1
2
3
4
C2H2Cl2
water
water
Rh2(OAc)4
Rh2(OAc)4
Rh2(pfb)4
3
24
24
24
88
0:1.1:1
a All reactions were carried out using 1e (0.15 mmol), Rh2(OAc)4 (1.0
mol %), and water (1.5 mL) at 80 °C for 24 h, followed by extraction with
Et2O and then reloaded with 1e. b Isolated yield of 2e after solvent
evaporation (pure by 1H NMR and TLC). c Observed conversion by 1H
NMR (1e, 80%; 2e, 20%).
85
0.6:0.15:1
0.5:0.5:1c
0.3:0.86:1c
68c
52c
water
Rh2(Ooct)4
a Isolated yield as a mixture of 3n, 3n′ and 4n (except for entry 1) after
purification by flash chromatography. b Observed selectivities of the crude
reaction mixture (by 31P NMR). c Reaction less clean; other minor unidenti-
fied peaks (17-23%) were observed by 31P NMR.
TABLE 9. Reuse of the Dirhodium(II) Catalyst Using 1 and 0.1
Mol % of Catalyst and the Substrate 1j
N-substituents in closer proximity to the reactive metalo-
carbenoid. With the diazo compound 1n, we expected that in
water the formation of the hydrophobic region would be
accomplished with the more hydrophobic n-butyl group and,
therefore, the insertion would take place preferentially in this
substituent. Interestingly, an increased selectivity in favor of
the γ-lactam 3n′ was achieved in water when compared with
that of the cyclization in C2H4Cl2, where a 1:1 ratio of 3n/3n′
was obtained (Table 6).
As already mentioned, water is a desirable solvent for
chemical reactions for reasons of cost, safety, and environmental
concerns; furthermore, the use of water as the solvent in this
particular transformation allows a simple, efficient, and robust
system for the Rh2(OAc)4 catalyst reuse. In fact, after the
cyclization of the model substrate 1a, the aqueous solution
containing the Rh2(OAc)4 catalyst and some traces of the diazo
1a was extracted with diethyl ether. To the remaining aqueous
solution containing the Rh2(OAc)4 was added more substrate
1a, and the process was repeated 11 times, after which an
erosion in the conversion was observed (Table 7).4d For a total
of 10 cycles, a high TON number of 883 was obtained. The
rhodium content in the organic phase of each cycle was also
determined by inductively coupled plasma atomic spectroscopy
(ICP). As can be seen, the rhodium catalyst is retained in the
recycled aqueous phase, because only 0.4-2.3% is lost to the
organic phase (Table 7). Surprisingly, when the cyclization of
the substrate 1e and the catalyst recycle were performed, only
four efficient cycles were achieved (Table 8). The efficiency
of the catalyst reuse is strongly dependent on the initial amount
of the catalyst used. A comparative study of the C-H insertion
of substrate 1j was performed in the presence of 1 mol % and
1 mol % catalyst
0.1 mol % catalyst
conversion after
26 ha (%)
conversion after
48 ha (%)
run
2j/3j
run
2j/3j
1
2
3
99
87
89
1:11
1:11
1:16
1
2
3
63
39
29
1:13
1:41
1:34
a Observed conversion by 31P NMR.
0.1 mol % of Rh2(OAc)4 (Table 9). Like expected, in the first
run the conversion decreases to 63% after 48 h in the presence
of 0.1 mol % versus the quantitative yield achieved in 26 h
when the 1 mol % of catalyst was used.
To exclude the hypothesis of a species formed by the reaction
of the rhodium dimer with water to be the catalyst of the
reaction, which possibly would not be extracted with ethyl ether,
dirhodium(II) tetraacetate was heated at 80 °C in water for 24
h, and after recrystallization in this solvent, a green solid similar
to the initial one was analyzed by microanalysis and was
determined to be Rh2(OAc)4‚2H2O. This recrystallized sample
was further used in the cyclization of substrate 1j, and after 26
h at 80 °C, a mixture of 2j and 3j (1:12) was obtained by
extraction with ethyl ether in 71% yield. The presence of Rh2-
(OAc)4‚2H2O goes in account with what was said above about
the complexation of the solvent with the axial positions of the
catalyst (Scheme 2).
J. Org. Chem, Vol. 71, No. 15, 2006 5493

Candeias et al.
1
hexane, 9:1). H NMR (CDCl3, ppm): δ 1.34 (t, J ) 7.0 Hz, 6H,
OCH2CH3), 4.09-4.26 (m, 4H, OCH2CH3), 4.90 (s, 2H, NCH2-
Ph), 7.06-7.33 (m, 10H, Ph). 13C NMR (CDCl3, ppm): δ 16.1
(OCH2CH3), 16.1 (OCH2CH3), 54.0 (NCH2Ph), 63.5 (OCH2CH3),
63.6 (OCH2CH3), 127.5, 127.9, 128.3, 128.3, 128.8, 129.8, 136.8,
In summary, the present study shows that Rh(II) carbenoids
derived from R-diazo-acetamides can originate â- and γ-lactams
via intramolecular C-H insertion in water. In more detail, this
study showed that the selectivity of the C-H insertion depends
on the structure of the catalyst and the hydrophobic nature of
the amide substituents. An appropriate balance between these
factors leads to a more hydrophobic environment around the
carbenoid center that reduces the competitive attack by the
water. The use of water as a solvent allows a simple, efficient,
and robust system for Rh2(OAc)4 catalyst reuse and opens
further applications on the use of Rh(II) carbenoid chemistry
for the synthesis of more complex molecules under conditions
potentially more environmentally friendly.
141.0 (Ph), 161.6 (d, J2
) 11.5 Hz, OCCN2PO). 31P NMR
C-P
(CDCl3, ppm): δ 14.0. IR (film): 3055, 2986, 2106, 1630, 1265,
1027 cm-1. MS (FAB+) m/z (%): 388, 359, 181. HRMS (FAB+)
calcd for C19H23N3O4P, 388.1426 [M + H]+; found, 388.1424 [M
+ H]+.
N-(n-Butyl)-N-(2-methoxyethyl)amine. Butyraldehyde (55.9
mmol) was added at room temperature in an argon atmosphere to
a mixture of 4 Å powder molecular sieves (20 g) and N-(2-
methoxyethyl)amine (39.9 mmol) in anhydrous dichloromethane
(100 mL) under vigorous stirring and allowed to react overnight.
The mixture was then filtered over a Celite pad and washed with
dichloromethane. After solvent removal under reduced pressure,
the residue was dissolved in anhydrous ethyl ether (140 mL), and
aluminum lithium hydride (80.0 mmol) was slowly added at 0 °C
under an argon atmosphere, stirring at this temperature for a while
and at room temperature during the night. Water was slowly added
(8 mL) until a white precipitate was formed, and the salt was filtered
and washed with ethyl ether. After solvent removal, the residue
was distilled at 30 °C/0.2 mmHg, yielding in 50% the desired amine
Experimental Section
Preparation of R-Diazo Compounds. The preparation of the
substrates not described was already described elsewhere (com-
pounds 1a, 2a, 1g-i, 2g, 3g-h, 1k-m, 3k, 2l, and 3m, described
in ref 4a; 1f and 2f in ref 4b; 1b and 2b in ref 15a; 1d, 2d, 1e, and
2e in ref 15b; and compounds 1c and 2c in ref 4d). The
p-toluenesulfonyl azide used was prepared from p-toluenesulfonyl
chloride and sodium azide, following a reported procedure.20 The
structural assignment of all new compounds was made by bidi-
mensional NMR techniques (COSY and HMQC).
Preparation of N-(Benzyl)-R-(diethoxyphosphoryl)-N-(phen-
yl)acetamide. R-Bromoacetyl bromide (18.9 mmol) was slowly
added at 0 °C to a solution of N-benzylphenylamine (16.4 mmol)
and anhydrous triethylamine (19.6 mmol) in anhydrous dicloro-
methane (25 mL) under an argon atmosphere. The mixture was
briefly stirred at 0 °C and then at room temperature for 2 h. The
reaction mixture was washed with 3 M HCl (20 mL), and the
aqueous layer was extracted with dichloromethane (3 × 4 mL).
The combined organic layers were washed with saturated NaHCO3
solution and then dried with Na2SO4. The residue was concentrated
under reduced pressure and used for the next reaction without
further purification.
1
as a colorless liquid. H NMR (CDCl3, ppm): δ 0.85 (t, J ) 7.3
Hz, 3H, NCH2CH2CH2CH3), 1.25-1.31 (m, 2H, NCH2CH2CH2-
CH3), 1.38-1.44 (m, 2H, NCH2CH2CH2CH3), 1.71 (s, 1H, HN-
(CH2CH2CH2CH3)(CH2CH2OCH3)), 2.55 (t, J ) 7.3 Hz, 2H,
NCH2CH2CH2CH3), 2.72 (t, J ) 5.2 Hz, 2H, NCH2CH2OCH3),
3.29 (s, 3H, NCH2CH2OCH3), 3.44 (t, J ) 5.2 Hz, 2H, NCH2CH2-
OCH3). 13C NMR (CDCl3, ppm): δ 13.9 (NCH2CH2CH2CH3), 20.4
(NCH2CH2CH2CH3), 32.1 (NCH2CH2CH2CH3), 49.3 (NCH2CH2-
CH2CH3), 49.6 (NCH2CH2OCH3), 58.7 (NCH2CH2OCH3), 71.9
(NCH2CH2OCH3). IR (film): 2958, 2929, 2873, 2825, 1460, 1113
cm-1. MS (CI) m/z: 71, 69, 59, 57, 55.
N-(n-Butyl)-R-(diethoxyphosphoryl)-N-(2-methoxyethyl)ace-
tamide. A solution of dicyclohexyl carbodiimide (4.2 mmol) in
anhydrous dichloromethane (10 mL) was slowly added at 0 °C
under an argon atmosphere to a solution of the starting amine (3.8
mmol) and diethylphosphonoacetic acid (4.2 mmol) in dichloro-
methane (25 mL), with dicyclohexyl urea (DCU) formation being
observed. After 4 h at room temperature, the mixture was filtered
over a Celite pad and concentrated under reduced pressure, and
the remaining DCU was precipitated in cold ethyl ether. After other
filtration over a Celite pad and concentration of the residue, this
was washed with saturated NaHCO3 solution, and the aqueous layer
was extracted with diethyl ether (2 × 10 mL). The combined
organic layers were dried with Na2SO4, filtered, and concentrated
under reduced pressure. After flash chromatography (acetone/
hexane, 1:5), N-(n-butyl)-R-(diethoxyphosphoryl)-N-(2-methoxy-
ethyl)acetamide was obtained as a colorless liquid in 75% yield.
Rf ) 0.38 (silica, acetone/hexane, 2:3). 1H NMR (CDCl3, ppm): δ
0.83-0.90 (m, 3H, NCH2CH2CH2CH3), 1.21-1.30 (m, 8H, NCH2-
CH2CH2CH3 and OCH2CH3, overlapped signals), 1.45-1.50 (m,
2H, NCH2CH2CH2CH3), 2.98 (d, JP-H ) 22.0 Hz, 2H, (EtO)2-
OPCH2CO, conformer), 3.12 (d, JP-H ) 21.8 Hz, 2H, (CH3CH2O)2-
OPCH2CO, conformer), 3.27 (s, 3H, NCH2CH2OCH3, conformer),
3.30-3.46 (m, 4H, NCH2CH2OCH3 and NCH2CH2CH2CH3, over-
lapped signals), 3.55 (t, J ) 5.15 Hz, 2H, NCH2CH2OCH3), 4.06-
4.16 (m, 4H, OCH2CH3). 13C NMR (CDCl3, ppm): δ 13.68, 13.72
(NCH2CH2CH2CH3, conformers), 16.16, 16.22 (OCH2CH3), 19.85,
19.90 (NCH2CH2CH2CH3, conformers), 29.4, 30.8 (NCH2CH2CH2-
CH3, conformers), 33.1 (d, JP-C ) 135.3 Hz, (CH3CH2O)2OPCH2-
CO, conformer), 33.5 (d, JP-C ) 133.1 Hz, (CH3CH2O)2OPCH2CO,
conformer), 46.1 (NCH2CH2OCH3), 48.3, 49.9 (NCH2CH2CH2CH3,
conformers), 58.7, 59.0 (NCH2CH2OCH3, conformers), 62.3-62.5
(m, OCH2CH3, conformers), 70.6 (NCH2CH2OCH3), 164.7, 165.0
(CH2CON, conformers). 31P NMR (CDCl3, ppm): δ 21.7, 22.2
(conformers). IR (film): 2960, 1643, 1456, 1250, 1117, 1053, 1026,
Triethyl phosphite (19.0 mmol) was added to a solution of
R-bromoacetamide (13.4 mmol) in anhydrous dichloromethane (13
mL) under an argon atmosphere. The mixture was heated at reflux
for 4 h and at room temperature during the night. The solvent was
removed under reduced pressure, and after flash chromatography
purification on silica gel, N-(benzyl)-R-(diethoxyphosphoryl)-N-
(phenyl)acetamide was obtained in 74% yield: orange oil, Rf )
0.26 (silica, AcOEt/hexane, 3:2). 1H NMR (CDCl3, ppm): δ 1.26
(t, J ) 7.1 Hz, 6H, OCH2CH3), 2.79 (d, JP-H ) 21.7 Hz, 2H, CCH2-
PO), 4.05-4.13 (m, 4H, OCH2CH3), 4.87 (s, 2H, NCH2Ph), 7.04-
7.31 (m, 10H, Ph). 13C NMR (CDCl3, ppm): δ 16.1 (OCH2CH3),
16.2 (OCH2CH3), 33.3 (d, JC-P ) 137.4 Hz, OCCH2PO), 53.1
(NCH2Ph), 62.2 (OCH2CH3), 62.3 (OCH2CH3), 127.2 (Ph), 128.2
(Ph), 128.4 (Ph), 128.5 (Ph), 129.5 (Ph), 136.8 (Ph), 141.9 (Ph),
164.7 (d, J2
) 4.6 Hz, OCCH2CO). 31P NMR (CDCl3, ppm):
C-P
δ 21.8. IR (film): 3053, 2985, 1655, 1265, 1028 cm-1. MS (FAB+)
m/z (%): 362, 182, 179. HRMS (FAB+) calcd for C19H25NO4P,
362.1521 [M + H]+; found, 362.1521 [M + H]+.
1j. p-Toluenesulfonyl azide (6.6 mmol) was slowly added to a
solution of N-(benzyl)-R-(diethoxyphosphoryl)-N-(phenyl)acetamide
(5.5 mmol) and sodium hydride (6.6 mmol) in anhydrous THF (81
mL) at 0 °C. After the addition, the mixture was stirred at room
temperature over a period of 2.5 h. Water (25 mL) and ethyl ether
(25 mL) were added, and the aqueous phase was extracted with
ethyl ether (5 × 25 mL). The organic layers were dried with Na2-
SO4, filtered, and concentrated under reduced pressure. After flash
chromatography on silica gel, the desired diazocompound was
obtained as a yellow oil in 71% yield. Rf ) 0.48 (silica, AcOEt/
(20) Deyrup, J. A.; Moyer, C. L. J. Org. Chem. 1969, 34, 175-179.
5494 J. Org. Chem., Vol. 71, No. 15, 2006

C-H Insertion of Diazo Substrates in Water
970 cm-1. MS (EI) m/z: 310, 179, 151, 130, 123, 98, 86. HRMS
(EI - ESI) m/z calcd for C13H28NNaO5P, 332.160 [M + Na]+;
found, 332.158 [M + Na]+.
m, NCH2CH2CH2CH3, overlapped signals), 1.20-1.32 (8H, m,
OCH2CH3 and NCH2CH2CH2CH3, overlapped signals), 1.37-1.48
(2H, m, NCH2CH2CH2CH3, overlapped signals), 2.94 (1H, d, JP-H
) 23.9 Hz, OPCH(CH)CO), 3.18-3.34 (7H, m, NCH2CH-
(OCH3)CH and NCH2CH2CH2CH3, overlapped signals), 4.10-4.19
1n. A solution of N-(n-butyl)-R-(diethoxyphosphoryl)-N-(2-
methoxyethyl)acetamide (1.9 mmol) in anhydrous THF (3 mL) was
slowly added at 0 °C in an argon atmosphere to a suspension of
sodium hydride (2.3 mmol) and p-toluenesulfonyl azide (2.3 mmol)
in THF (12 mL). The mixture was stirred at this temperature for 1
h and at room temperature overnight. Water (10 mL) and ethyl
ether (10 mL) were added, and the aqueous phase was extracted
with ethyl ether (4 × 10 mL). The combined organic layers were
dried with Na2SO4, filtered, and concentrated under reduced
pressure. The desired compound 1n was obtained as a yellow oil
in 70% yield after flash chromatography (silica gel, AcOEt/hexane,
2:3). Rf ) 0.33 (silica, AcOEt/hexane, 1:1). 1H NMR (CDCl3,
ppm): δ 0.90 (t, J ) 7.3 Hz, 3H, NCH2CH2CH2CH3), 1.23-1.35
(m, 8H, NCH2CH2CH2CH3 and OCH2CH3, overlapped signals),
1.49-1.56 (m, 2H, NCH2CH2CH2CH3), 3.30 (s, 3H, NCH2CH2-
OCH3), 3.36 (t, J ) 7.8 Hz, 2H, NCH2CH2CH2CH3), 3.51 (s, 4H,
NCH2CH2OCH3 and NCH2CH2OCH3, overlapped signals), 4.13-
4.23 (m, 4H, OCH2CH3). 13C NMR (CDCl3, ppm): δ 13.7 (NCH2-
CH2CH2CH3), 16.02, 16.07 (OCH2CH3), 19.9 (NCH2CH2CH2CH3),
30.1 (NCH2CH2CH2CH3), 47.2 (NCH2CH2OCH3), 48.5 (NCH2CH2-
CH2CH3), 58.8 (NCH2CH2OCH3), 63.4, 63.5 (OCH2CH3), 70.6
(NCH2CH2OCH3), 162.3 (N2CCON). 31P NMR (CDCl3): δ 13.8
ppm. IR (film): 2960, 2933, 2100, 1624, 1419, 1259, 1119, 1018,
974 cm-1. MS (CI) m/z: 336, 308, 280, 130. HRMS (EI - ESI)
m/z calcd for C13H26N3NaO5P, 358.150 [M + Na]+; found, 358.151
[M + Na]+.
General Procedure for the Cyclization of 1a, Followed by
31P NMR. A solution of Rh2(OAc)4 (1 mol %) dissolved in the
reaction solvent (0.5 mL) was added, at room temperature without
an argon atmosphere, to a NMR tube containing the diazocompound
1a (75 µmol) and a capillary tube filled with deuterated chloroform.
Right after the catalyst addition, the first spectrum was made and
the consequents in 10, 15, or 20 min intervals over a period of
approximately 8 h. Wet chloroform was prepared by adding 0.5
mL water to 1.0 mL chloroform, followed by organic layer removal.
Dirhodium-Catalyzed Decomposition of R-Diazo-R-(diethoxy-
phosphoryl)-acetamides in Organic Solvents. The general pro-
cedures for the transformations of dirhodium-catalyzed R-diazo-
R-(diethoxyphosphoryl)-acetamides were followed according to the
general procedure already described.4a
(5H, NCH2CH(OCH3)CH and OCH2CH3, overlapped signals). 13
C
NMR (CDCl3, ppm): δ 13.5 (NCH2CH2CH2CH3), 16.18, 16.24
(OCH2CH3 and NCH2CH2CH2CH3, overlapped signals), 19.6
(NCH2CH2CH2CH3), 42.7 (NCH2CH(OCH3)CH), 47.8 (OPCH-
(CH)CO), 52.6 (NCH2CH2CH2CH3, overlapped signals), 56.2
(OCH3), 62.0-63.2 (OCH2CH3, overlapped signals), 75.0 (OPCH-
(CH)CO), 167.1 (CdO). 31P NMR (CDCl3): δ 21.0 ppm. IR
(film): 2962, 2931, 1689, 1244, 1051, 1022, 970 cm-1. MS (CI)
m/z: 308, 276. HRMS (EI - ESI) m/z calcd for C13H26NNaO5P,
330.144 [M + Na]+; found, 330.144 [M + Na]+.
Decomposition of 1j by Rh2(OAc)4 Catalyst in Dichloroeth-
ane. After the consumption of all of the diazo compound 1j (24 h,
confirmed by TLC) and solvent removal, the reaction products were
purified by flash chromatography (basic alumina, AcOEt/hexane).
Compounds 2j and 3j were obtained in 50% yield as a mixture of
2j/3j (1:2). One part of the mixture was purified by flash
chromatography on silica gel to achieve pure 3j (decompose in
alumina), and the other part was purified in basic alumina to achieve
pure 2j (decompose in silica gel). 3j: Rf ) 0.38 (silica, AcOEt/
1
hexane, 7:3). H NMR (CDCl3, ppm): δ 1.09 (t, J ) 7.6 Hz, 3H,
OCH2CH3), 1.42 (t, J ) 7.5, 3H, OCH2CH3), 3.93-4.09 (m, 2H,
OCH2CH3), 4.18 (d, JP-H ) 29.9 Hz, 1H, CHCO(PO)), 4.25-4.32
(m, 2H, OCH2CH3), 4.75 (d, J ) 15.7 Hz, 1H, NCH2Ph), 5.12 (d,
J ) 15.7 Hz, 1H, NCH2Ph), 6.71 (d, J ) 7.8 Hz, 1H, NCCHCH),
7.04 (t, J ) 7.6 Hz, 1H, NC(CH)2CH), 7.18-7.31 (m, 6H, Ph,
NCCHCH), 7.55 (d, J ) 7.3 Hz, 1H, NCCCHCH). 13C NMR
(CDCl3, ppm): δ 16.1 (d, J3
) 5.5 Hz, OCH2CH3), 16.3 (d,
C-P
J3C-P ) 6.0 Hz, OCH2CH3), 43.9 (NCH2Ph), 46.3 (d, JC-P ) 135.9
Hz, CHCO(PO)), 63.1 (d, J2
) 6.4 Hz, OCH2CH3), 63.8 (d,
C-P
J2
) 6.2 Hz, OCH2CH3), 109.1 (NCCHCH), 122.7 (NC-
C-P
(CH)2CH), 127.0 (Ph), 127.2 (NCCHCH), 128.7, 135.5 (Ph), 143.7
(NCCH), 170.3 (CdO). 31P NMR (CDCl3): δ 17.5 ppm. IR
(film): 3055, 2986, 1712, 1611, 1265, 1023 cm-1. MS (FAB+)
m/z (%): 360, 223, 136. HRMS (FAB+) calcd for C19H22NO4P,
359.129 [M]+; found, 359.129 [M]+. 2j: Rf ) 0.67 (neutral alumina,
AcOEt/hexane, 2:3). 1H NMR (CDCl3, ppm): δ 1.34 (m, 6H,
OCH2CH3), 3.55 (dd, JH-P ) 15.6, JH-H ) 2.7 Hz, 1H, NCOCH-
CHPh), 4.14-4.32 (m, 4H, OCH2CH3), 5.22 (dd, J3P-H ) 9.2 Hz,
JH-H ) 2.7 Hz, 1H, NCOCHCHPh), 7.06 (t, J ) 6.9 Hz, 1H, Ph),
7.23-7.37 (m, 9H, Ph). 13C NMR (CDCl3, ppm): δ 16.4
(OCH2CH3), 55.8 (NCOCHCHPh), 57.2 (d, JC-P ) 145.0 Hz,
NCOCHCHPh), 62.8, 63.1 (OCH2CH3), 117.0, 124.3, 125.9, 128.9,
Decomposition of 1n by Rh2(OAc)4 Catalyst in Dichloroeth-
ane. After consumption of all of the diazo compound (3 h,
confirmed by TLC) and solvent removal, the reaction products were
purified by flash chromatography (silica, AcOEt/hexane). A mixture
of 3n′ and 3n (1:1.3) was obtained in 88% yield. It was observed
that decomposition of 3n occurred in basic alumina and a partial
decomposition occurred in silica. Further purification of one part
resulted in the isolation of 3n′, while 3n was characterized as a
mixture of both products. 3n′: Rf ) 0.36 (basic alumina, AcOEt/
129.0, 129.3, 136.5 (Ph), 136.5 (quaternary Ph), 159.1 (CdO). 31
P
NMR (CDCl3): δ 18.3 ppm. IR (film): 3063, 2984, 2926, 1758,
1500, 1383, 1259, 1024 cm-1. MS (FAB+) m/z (%): 360, 331,
182. HRMS (FAB+) calcd for C19H23NO4P, 360.136 [M + H]+;
found, 360.137 [M + H]+.
1
Decomposition of 1j by Rh2(pfb)4 Catalyst in Dichloroethane.
After the consumption of all of the diazo compound 1j (6 h,
confirmed by TLC) and solvent removal under reduced pressure,
the reaction mixture dissolved in dichloromethane, filtered over a
Celite pad, and evaporated to dryness giving 3j in 97% yield.
Decomposition of 1j by Rh2(OAc)4 Catalyst in Benzene.
Compound 1j (0.154 mmoL) was added to a solution of Rh2(OAc)4
(1 mol %) in benzene (1.5 mL) under an argon atmosphere and
heated at 80 °C over a period of 24 h. Water was added (2 mL),
and the aqueous phase was extracted with ethyl ether (2 × 1.5 mL).
After solvent evaporation under reduced pressure, a mixture of
products (2j/3j, 1:11.6) was obtained in 88% yield.
Decomposition of 1j by Rh2(OAc)4 Catalyst in Perfluoro-
decaline. Compound 1j (0,154 mmoL) was added to a suspension
of Rh2(OAc)4 (1mol %) in perfluorodecaline (1.5 mL) under an
argon atmosphere and heated at 80 °C over a period of 24 h. After
solvent removal at 34 °C (1 mm Hg), water and ethyl ether were
hexane, 7:3). H NMR (CDCl3, ppm): δ 0.92 (3H, t, J ) 7.3 Hz,
NCH2CH(CH2CH3)CH), 1.30-1.35 (6H, m, OCH2CH3), 1.39-1.50
(1H, m, NCH2CH(CH2CH3)CH), 1.60-1.64 (1H, m, NCH2CH(CH2-
CH3)CH), 2.53-2.59 (1H, m, NCH2CH(CH2CH3)CH), 3.12 (1H,
d, JH-P ) 9.6 Hz, OCCH(CH)PO), 3.31 (3H, s, OCH3), 3.44-
3.49 (5H, m, NCH2CH2OCH3 and NCH2CH(CH2CH3)CH, over-
lapped signals), 3.72 (1H, t, J ) 8.7 Hz, NCH2CH(CH2CH3)CH),
4.12-4.23 (4H, m, OCH2CH3). 13C NMR (CDCl3, ppm): δ 10.8
(NCH2CH(CH2CH3)CH), 16.4 (OCH2CH3), 28.1, 29.6 (NCH2CH-
(CH2CH3)CH), 35.1 (NCH2CH(CH2CH3)CH), 42.8 (NCH2CH2-
OCH3), 47.2 (d, JC-P ) 141.1 Hz, OPCH(CH)CO), 52.7 (NCH2-
CH(CH2CH3)CH), 58.6 (OCH3), 62.1, 63.0 (OCH2CH3), 70.7
(NCH2CH2OCH3), 168.9 (CdO). 31P NMR (CDCl3): δ 24.3 ppm.
IR (film): 2964, 2931, 1689, 1265, 1026, 972 cm-1. MS (CI) m/z:
308. HRMS (EI - ESI) m/z calcd for C13H26NNaO5P, 330.144 [M
+ Na]+; found, 330.144 [M + Na]+. 3n: Rf ) 0.5 (basic alumina,
1
AcOEt/hexane, 4:1). H NMR (CDCl3, ppm): δ 0.84-0.92 (3H,
J. Org. Chem, Vol. 71, No. 15, 2006 5495

Candeias et al.
added. After extraction with ethyl ether (2 × 1.5 mL) and solvent
removal, a mixture of products (2j/3j, 1:7) was obtained in 79%
yield.
Decomposition of 1m in Water in the Presence of Rh2(OAc)4.
After consumption of all the diazo compound (0.68 mmol, 48 h,
confirmed by TLC) and solvent removal, the reaction products were
purified by flash chromatography (basic alumina, AcOEt/hexane),
yielding 86% of a mixture of products (3m/4m, 1:2.7). One part
of the previous mixture was purified again on basic alumina (partial
decomposition was observed) to obtain 4m has a brown oil. 4m:
Rf ) 0.14 (neutral alumina, AcOEt/MeOH, 3:2). 1H NMR (CDCl3,
ppm): δ 1.21-1.29 (6H, m, OCH2CH3), 2.78 (2H, t, J ) 7.2 Hz
HNCH2CH2Ph), 3.50-3.55 (2H, m, NCH2CH2Ph), 3.95-4.18 (4H,
m, OCH2CH3), 4.35 (1H, d, JP-H ) 12.4 Hz, OPCHOHCO), 6.99
(1H, s, HNCH2CH2Ph), 7.13-7.25 (5H, m, Ph). 13C NMR (CDCl3,
ppm): δ 16.3, 16.4 (OCH2CH3), 35.5 (NCH2CH2Ph), 41.2 (NCH2-
CH2Ph), 63.8, 63.9 (OCH2CH3), 67.9 (d, JC-P ) 156.1 Hz,
POCHOHCO), 126.6, 128.6, 128.7 (Ph), 138.4 (quaternary Ph),
167.3 (CdO). 31P NMR (CDCl3): δ 18.2 ppm. IR (film): 3286,
2983, 2933, 1666, 1533, 1238, 1026, 976 cm-1. MS (CI) m/z: 316,
178, 139, 104. HRMS (EI - ESI) m/z calcd for C14H22NNaO5P,
338.113 [M + Na]+; found, 338.113 [M + Na]+.
Decomposition of 1m in Water in the Presence of Rh2(pfb)4.
After consumption of all the diazo compound (0.154 mmol, 24 h,
confirmed by TLC) and solvent removal, the reactions products
were purified by flash chromatography (basic alumina, AcOEt/
hexane), yielding 64% of a mixture of products 3m/4m (12:1).
Decomposition of 1m in Water in the Presence of Rh2(Ooct)4.
After consumption of all the diazo compound (0.154 mmol, 24 h,
confirmed by TLC) and solvent removal, the mixture was purified
by flash chromatography (basic alumina, AcOEt/hexane), yielding
76% of 3m.
Decomposition of 1a in Water. A solution of 1a (0.15 mmol)
was heated at 80 °C over a period of 70 h in water (1.5 mL). After
solvent removal, 4a was obtained and fully characterized without
further purification. Rf ) 0.38 (silica, AcOEt/hexane, 7:3). 1H NMR
(CDCl3, ppm): δ 1.12 (6H, d, J ) 6.5 Hz, NCH(CH3)2), 1.25 (6H,
d, J ) 5.6 Hz, NCH(CH3)2), 1.31-1.39 (6H, m, OCH2CH3), 3.45-
3.52 (1H, m, NCH(CH3)2), 3.92 (s, 1H, CHOH), 4.02-4.21 (5H,
m, NCH(CH3)2 and OCH2CH3, overlapped signals), 4.65 (1H, d,
JH-P ) 7.6 Hz, POCHOHCO). 13C NMR (CDCl3, ppm): δ 16.3
(OCH2CH3), 19.7, 19.9, 20.4, 20.7 (NCH(CH3)2), 46.8, 48.7 (NCH-
(CH3)2), 63.3, 63.5 (OCH2CH3), 67.0 (d, JC-P ) 153.0 Hz,
POCHOHCO), 166.1 (CdO). 31P NMR (CDCl3): δ 16.9 ppm. IR
(film): 3391, 3055, 1640, 1266, 1039 cm-1. MS (FAB+) m/z (%):
296, 278, 254, 158, 137. HRMS (FAB+) calcd for C12H27NO5P,
296.163 [M + H]+; found, 296.162 [M + H]+.
General Procedure for the Dirhodium(II)-Catalyzed Decom-
position of R-Diazo Compounds in Water. To a solution of the
dirhodium(II) catalyst (1.0 mol %) in water (1.5 mL) was added
the appropriate diazo compound (0.154 mmol). The reaction mixture
was heated at 80 °C until the disappearance of the substrate
(determined by TLC). The mixture was concentrated under reduced
pressure and the residue was purified by flash chromatography
(basic/neutral alumina or silica with AcOEt/hexane), yielding the
desired compounds.
Decomposition of 1f in Water in the Presence of Rh2(OAc)4.
After consumption of all the diazo compound (24 h confirmed by
TLC) and solvent removal, the reaction crude mixture was purified
by PTLC (basic alumina, AcOEt/hexane, 3:2), and the product 2f
(described elsewhere4b) was obtained as a mixture of trans and cis
isomers (6:1) in 40% yield.
Decomposition of 1g in Water in the Presence of Rh2(OAc)4.
After consumption of all the diazo compound (18 h, confirmed by
TLC) and solvent removal, the reaction crude mixture was purified
by flash chromatography (basic alumina, AcOEt/hexane), and 2g
and 3g (described elsewhere4a) were obtained as a mixture in a
1:10 ratio in 97% yield.
Decomposition of 1k in Water in the Presence of Dirhodium-
(II) Catalyst. After consumption of all the diazo compound (0.154
mmol, 48 h, confirmed by TLC) in the presence of Rh2(OAc)4, the
reaction mixture was concentrated under reduced pressure and
purified by flash chromatography (basic alumina, AcOEt/MeOH),
yielding 71% of 4k as a yellow oil.
When Rh2(pfb)4 or Rh2(Ooct)4 was used, after consumption of
all the diazo substrate (24 h), the mixture of products was
chromatographed (basic alumina or silica, AcOEt/MeOH), yielding
the mixture of products in 73% (3k4a/4k, 1:1.1) and 62% yield (3k/
4k, 1:4.2), respectively. 4k: Rf ) 0.13 (silica, AcOEt/hexane, 7:3).
1H NMR (CDCl3, ppm): δ 1.27-1.33 (m, 6H, POCH2CH3), 3.29
(s, 6H, OCH3), 3.45-3.64 (m, 8H, NCH2CH2O), 4.15-4.23 (m,
4H, OCH2CH3), 4.53 (d, JP-H ) 18.22 Hz, 1H, COCH(OH)PO).
13C NMR (CDCl3, ppm): δ 15.3 (POCH2CH3), 47.2 (NCH2CH2O),
48.0 (NCH2CH2O), 58.8 (OCH3), 63.1 (POCH2CH3), 63.6 (POCH2-
CH3), 70.8 (NCH2CH2O), 74.0 (d, JP-C ) 159 Hz, COCH(OH)-
PO), 163.2 (NCOCH(OH)). 31P NMR (CDCl3): δ 16.7 ppm. IR
(film): 3423, 3054, 2986, 1657, 1422, 1265, 1047 cm-1. MS
(FAB+) m/z (%): 296, 268, 137. HRMS (FAB+) calcd for
C12H27NO7P, 328.153 [M]+; found, 328.152 [M]+.
Decomposition of 1h in Water in the Presence of Rh2(OAc)4.
After consumption of all the diazo compound (29 h, confirmed by
TLC) and solvent removal, the reaction crude mixture was purified
by flash chromatography (basic alumina, AcOEt/hexane), and the
product 3h4a was obtained in 59% yield.
Decomposition of 1l in Water in the Presence of Rh2(OAc)4.
After consumption of all the diazo compound (24 h, confirmed by
TLC) and solvent removal, the reaction products were isolated by
flash chromatography (silica, AcOEt/hexane). 2l4a was obtained in
57% yield and 4l was obtained in 25% yield. 4l: Rf ) 0.2 (silica,
1
AcOEt/hexane, 4:1), H NMR (CDCl3, ppm): δ 1.25-1.70 (6H,
Decomposition of 1n in Water in the Presence of Dirhodium-
(II) Catalyst. After consumption of all the diazo compound (0.154
mmol, 24 h, confirmed by TLC) in the presence of dirhodium
catalyst, the reaction mixture was concentrated under reduced
pressure and chromatographed (silica, AcOEt/hexane). A different
mixture of products was obtained depending on the used catalyst.
4n was characterized from a mixture of 4n and 3n′ in a 0.8:1 ratio.
4n: Rf ) 0.13 (basic alumina, AcOEt/hexane, 4:1). 1H NMR
(CDCl3, ppm): δ 0.865 (t, J ) 7.3 Hz, 3H, NCH2CH2CH2CH3,
overlapped signals), 1.18-1.31 (m, 8H, OCH2CH3 and NCH2-
CH2CH2CH3, overlapped signals), 1.50 (t, J ) 7.6 Hz, 2H,
NCH2CH2CH2CH3, overlapped signals), 3.26-3.44 (m, 7H, OCH3,
NCH2CH2OCH3, NCH2CH2CH2CH3, overlapped signals), 3.75-
3.81 (m, 1H, NCH2CH2OCH3), 4.07-4.25 (m, 5H, OCH2CH3 and
NCH2CH2OCH3, overlapped signals), 4.49 (d, JJP-H ) 18.1 Hz,
1H, OPCH(OH)CO). 13C NMR (CDCl3, ppm): δ 13.6 (NCH2CH2-
CH2CH3), 16.3 (POCH2CH3), 19.8 (NCH2CH2CH2CH3), 28.8
(NCH2CH2CH2CH3), 42.7 (NCH2CH2OCH3), 46.7 (NCH2CH2-
CH2CH3), 58.5 (OCH3), 62.86, 62.92, 63.08, 63.14 (OCH2CH3,
m, OCH2CH3), 4.07-4.34 (4H, m, OCH2CH3), 4.51-4.52 (3H, m,
POCHOHCO and NCH2Ph, overlapped signals), 7.26-7.36 (5H,
m, Ph). 13C NMR (CDCl3, ppm): δ 16.3 (OCH2CH3), 43.9 (NCH2-
Ph), 64.1 (OCH2CH3), 68.0 (d, JC-P ) 156.1 Hz, POCHOHCO),
127.6, 127.7, 128.7 (Ph), 137.4 (quaternary Ph), 167.4 (CdO). 31
P
NMR (CDCl3): δ 18.2 ppm. IR (film): 3299, 2983, 2929, 1666,
1531, 1454, 1238, 1026, 976 cm-1. MS (CI) m/z: 302, 286, 139,
91. HRMS (EI - ESI) m/z calcd for C13H20NNaO5P, 324.144 [M
+ Na]+; found, 324.097 [M + Na]+.
Decomposition of 1l in Water in the Presence of Rh2(pfb)4
or Rh2(Ooct)4. After consumption of all the diazo compound (0.154
mmol, 24 h, confirmed by TLC) in the presence of rhodium catalyst
and solvent evaporation under reduced pressure, the reaction mixture
was purified by flash chromatography (basic alumina, AcOEt/
hexane). When Rh2(pfb)4 was used, 2l was obtained in 84% yield.
In the case of cyclization catalyzed by Rh2(Ooct)4 and purification
by flash chromatography (basic alumina, AcOEt/hexane), 2l was
obtained in 97% yield.
5496 J. Org. Chem., Vol. 71, No. 15, 2006

C-H Insertion of Diazo Substrates in Water
NCH2CH2OCH3), 74.0 (d, JP-C ) 159.4 Hz, COCH(OH)PO), 162.8
(CdO). 31P NMR (CDCl3): δ 16.9 ppm. IR (film): 3458, 2962,
2933, 1654, 1242, 1024, 974 cm-1. MS (CI) m/z 294.
Decomposition of 1j in Water in the Presence of Rh2(OAc)4.
After consumption of all the diazo compound (0.154 mmol, 26 h,
confirmed by TLC) in the presence of Rh2(OAc)4, the reaction
mixture was extracted with ethyl ether (5 × 1.5 mL), and after
solvent evaporation under reduced pressure, a mixture of products
(2j/3j, 1:10) was obtained in 97% yield.
Decomposition of 1j in Water in the Presence of Rh2(pfb)4
or Rh2(Ooct)4. After consumption of all the diazo compound (0.154
mmol, 48 h, confirmed by TLC) in the presence of rhodium catalyst
and solvent evaporation under reduced pressure, the reaction mixture
was filtered over a Celite pad. When Rh2(pfb)4 was used, 3j was
obtained in quantitative yield. After cyclization, catalyzed by Rh2-
(Ooct)4, and filtration, a mixture of products (2j/3j, 1:6) was
obtained in 92% yield.
Decomposition of 1j in Water in the Presence of Rh2(OAc)4
and Sodium Chloride. After dissolution of Rh2(OAc)4 (1 mol %)
in an aqueous solution (1.5 mL) of sodium chloride (20 wt %), the
diazo compound was added and heated at 80 °C over a period of
24 h. The reactions products were extracted with ethyl ether (5 ×
1.5 mL), and after solvent evaporation, a mixture of 2j/3j (1:21)
was obtained in 87% yield.
Decomposition of 1i in Water in the Presence of Rh2(OAc)4.
After consumption of all the diazo compound (0.154 mmol, 24 h,
confirmed by TLC) in the presence of Rh2(OAc)4, the reaction
mixture was concentrated under reduced pressure and purified by
PTLC (silica, AcOEt/hexane, 95:5), yielding 78% of 4i as a yellow
oil. Rf ) 0.35 (silica, AcOEt/hexane, 95:5). 1H NMR (CDCl3,
ppm): δ 0.95 (t, J ) 7.4 Hz, 3H, OCH2CH2CH3), 1.32 (t, J ) 7.1
Hz, 6H, POCH2CH3), 1.65-1.74 (m, 2H, OCH2CH2CH3), 4.15-
4.26 (m, 6H, OCH2CH2CH3, POCH2CH3, overlapped signals), 4.53
(d, JP-H ) 15.8 Hz, 1H, COCH(OH)PO). 13C NMR (CDCl3,
ppm): δ 10.1 (OCH2CH2CH3), 16.26, 16.31 (POCH2CH3), 21.8
(OCH2CH2CH3), 63.4-63.8 (POCH2CH3), 68.1 (OCH2CH2CH3),
68.7 (d, JP-C ) 155.0 Hz, COCH(OH)PO), 169.5 (CdO). 31P NMR
(CDCl3): δ 16.1 ppm. IR (film): 3427, 3056, 2984, 1740, 1266,
1089, 1025 cm-1. MS (FAB+) m/z (%): 255, 239, 167, 137. HRMS
(FAB+) calcd for C9H19O6P, 225.100 [M]+; found, 255.100 [M]+.
Procedure for Rh2(OAc)4 Recycling. To a solution of dirho-
dium(II) tetraacetate (1.0 mol %) in water (1.5 mL) was added 1a
(0.154 mmol), 1e, or 1j. The reaction mixture was heated at 80 °C
for 24 h, the product was extracted from the reaction medium with
Et2O (10 × 1.5 mL), and more substrate was added (0.154 mmol)
to the system.
Procedure for Catalyst Stability Determination. Dirhodium-
(II) tetraacetate (0.0453 mmol) was heated in water (43 mL) at 80
°C for 24 h, and after concentration under vacuum, the product
was recrystallized in water. The green solid obtained (9.6 mg) was
identified by microanalysis as being Rh2(OAc)4‚2H2O. Anal. Calcd
for C8H16O10Rh2: C, 20.10; H, 3.37. Found: C, 20.31; H, 3.35.
This sample was used for cyclization of 1j, according to the
procedure described earlier. The diazo compound (0.154 mmol)
was added to a solution of dirhodium(II) tetraacetate (1 mol %) in
water (1.5 mL), and the mixture was heated at 80 °C, under stirring,
for 26 h. The reaction products were extracted with Et2O (3 × 1.5
mL), and a mixture of products (2j/3j, 1:12) was obtained in 71%
yield.
Acknowledgment. We thank the Fundac¸a˜o para a Cieˆncia
e Tecnologia and FEDER for the financial support.
Supporting Information Available: Spectral data for all new
compounds and crude spectral data for the reaction of 1j in water
for different catalysts. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO060397A
J. Org. Chem, Vol. 71, No. 15, 2006 5497