The bis(trimethylsilyl)methyl group as an effective N-protecting group and site-selective control element in rhodium(II)-catalyzed reaction of diazoamides

Article abstract of DOI:10.1021/jo051042e

The intramolecular rhodium(II)-carbenoid-mediated C-H insertion reaction of structurally varied N-bis(trimethylsilyl)methyl,N-substituted diazoamides is studied. It has been found that in tertiary diazoamides the N- bis(trimethylsilyl)methyl (N-BTMSM) group is effective for conformational control about the amide N-C(O) bond; C-H insertion occurs at the other N-substituent. In Cα-branched diazoamides, the N-BTMSM is found also to exert its influence on the conformational preference about the N-C _α bond, which affects the regioselectivity of the C-H insertion in these systems. In unbranched diazoamides, inherent electronic effects of the N-substituent affect the regio- and chemoselectivity of the reaction; however, in branched diazoamides, electronic effects of the N-substituent and the α-substituent at the carbenoid carbon are subtle, but important in the deciding the eventual outcome of the reaction.

Full text of DOI:10.1021/jo051042e

The Bis(trimethylsilyl)methyl Group as an Effective N-Protecting
Group and Site-Selective Control Element in
Rhodium(II)-Catalyzed Reaction of Diazoamides
Andrew G. H. Wee* and Sammy C. Duncan
Department of Chemistry and Biochemistry, University of Regina,
Regina, Saskatchewan S4S 0A2, Canada
andrew.wee@uregina.ca
Received May 24, 2005
The intramolecular rhodium(II)-carbenoid-mediated C-H insertion reaction of structurally varied
N-bis(trimethylsilyl)methyl,N-substituted diazoamides is studied. It has been found that in tertiary
diazoamides the N-bis(trimethylsilyl)methyl (N-BTMSM) group is effective for conformational
control about the amide N-C(O) bond; C-H insertion occurs at the other N-substituent. In CR-
branched diazoamides, the N-BTMSM is found also to exert its influence on the conformational
preference about the N-CR bond, which affects the regioselectivity of the C-H insertion in these
systems. In unbranched diazoamides, inherent electronic effects of the N-substituent affect the
regio- and chemoselectivity of the reaction; however, in branched diazoamides, electronic effects of
the N-substituent and the R-substituent at the carbenoid carbon are subtle, but important in the
deciding the eventual outcome of the reaction.
Introduction
carbenoid attack at both N-substituents.3 This complica-
tion is especially pronounced in C-H insertion reactions
of R-diazoamides.1
R-Diazoamides undergo a number of interesting reac-
tions in the presence of a catalytic amount of di-
rhodium(II) complexes.1 Among them, the intramolecular
dirhodium(II) carbenoid mediated C-H insertion reac-
tion,1 cyclopropanation,2a and ylide formation/cycloaddi-
tion or rearrangement reactions2b are the most exploited
reactions especially for the preparation of structurally
diverse heterocycles. Steric, electronic, and conforma-
tional factors inherent in the diazo reactant as well as
the nature of Rh(II) catalysts have been shown to play
important roles in governing the regio-, chemo-, and
stereoselectivity of the transformations.1 It is also rec-
ognized that for acyclic, tertiary R-diazoamides,1 confor-
mational effects about the amide N-C(O) bond govern
site selectivity and, consequently, mixtures of lactam
products are usually obtained arising from metallo-
Two main strategies have been investigated for im-
proving site selectivity in the reactions of tertiary diazo-
amides. The first approach involves replacing one of the
two N-substituents in the tertiary diazoamide with a
bulky group3a,d,4 (e.g., tert-butyl, neopentyl, 2,4,6-tri-
methylbenzyl), which serves to bias the conformational
preference about the amide N-C(O) moiety, thereby
promoting metallocarbenoid reaction at the remaining
N-substituent. This strategy has proved useful but some
limitations5 have been encountered; for example, the
(3) See, for example: (a) Doyle, M. P.; Shanklin, M. S.; Oon, S. M.;
Pho, H. Q.; van der Heide, F. R.; Veal, W. R. J. Org. Chem. 1988, 53,
3384. (b) Moody, C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.;
Richards, I. C. Tetrahedron 1998, 54, 9689. (c) Miah, S.; Slawin, A. M.
Z.; Moody, C. J.; Sheehan, S. M.; Marino, J. P., Jr.; Semones, M. A.;
Padwa, A.; Richards, I. C. Tetrahedron 1996, 52, 2489. (d) Zaragoza,
F. Tetrahedron 1995, 51, 8829.
(4) (a) N-(tert-Butyl): Watanabe, N.; Anada, M.; Hashimoto, S.-i.;
Ikegami, S. Synlett, 1994, 1031. (b) N-(Neopentyl): Doyle, M. P.;
Pieters, R. J.; Taunton, J.; Pho, H. Q.; Padwa, A.; Hertzog, D. L.;
Precedo, L. J. Org. Chem. 1991, 56, 820. (c) N-(2,4,6-Trimethyl-
benzyl): Yoon, C. H.; Nagle, A.; Chen, C.; Gandhi, D.; Jung, K. W.
Org. Lett. 2003, 5, 2259. (d) N-Cumyl: Chen, Z.; Chen, Z.; Jiang, Y.;
Hu, W. Synlett 2004, 1763.
(1) Reviews: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds;
Wiley: New York, 1998. (b) Davies, H. M. L.; Beckwith, R. E. J. Chem.
Rev. 2003, 103, 2861. (c) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org.
Chem. 2004, 3773. (d) Merlic, C. A.; Zechman, A. L. Synthesis 2003,
1137.
(2) (a) Muthusamy, S.; Gunanathan, C. Synlett 2003, 1599. (b)
Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
10.1021/jo051042e CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/10/2005
8372
J. Org. Chem. 2005, 70, 8372-8380

Bis(trimethylsilyl)methyl Group as an Effective N-Protecting Group
SCHEME 1. Preparation of Diazoacetamides 4-6
N-tert-butyl is susceptible to metallocarbenoid C-H
insertion at one of the methyl groups,5a and the removal
of the tert-butyl group from the lactam product(s) is often
difficult.5b The second approach involves the use of a
group that is electronically deactivated toward C-H
insertion thereby favoring metallocarbenoid attack at the
remaining N-substituent.4b,6
We have reported7 the successful use of the p-meth-
oxyphenyl (PMP) group in Rh(II)-catalyzed C-H inser-
tion reaction of diazoamides wherein preferential met-
allocarbenoid attack at the N-“alkyl” substituent is
observed. However, subsequent studies8 have revealed
that in cases where metallocarbenoid C-H insertion at
the N-“alkyl” substituent was difficult due to electronic
deactivation and/or steric hindrance at the reaction site,
metallocarbenoid attack on the N-PMP was favored,
which resulted in the formation of oxindole derivatives
as major products. Our ongoing interest in achieving
control on the site selectivity in the reaction of diazo-
amides has led us to investigate the Rh(II)-catalyzed
reaction of N-bis(trimethylsilylmethyl)diazoamides.9 We
wished to determine (1) whether the N-bis(trimethyl-
silyl)methyl (N-BTMSM) group would afford effective
conformational control about the amide N-C(O) bond
thereby improving site-selectivity and (2) whether the
N-BTMSM group would influence the conformational
preference about the N-CR (sp3) sigma bond of the
second, branched N-substituent. We were encouraged by
literature reports10 on the chemical versatility of the
BTMSM group and its use as a N protecting group.11
Nonetheless, the use of the BTMSM group under met-
allocarbenoid reaction conditions has not been investi-
gated.
a Reagents and conditions: (a) for 1a,b d-h: (route A) RBr,
Na2CO3, NaI, DMF, 65 °C or (route B) ketone/aldehyde, Et2O,
NaBH4, MeOH, rt; for 1c: CH2dCHCO2Me, MeOH, rt, 24 h; (b)
diketene, DMAP, THF; (c) MsN3, DBU, MeCN; (d) LiOH‚H2O, aq
THF or 5% aq KOH, MeCN; (e) MeO2CCN2COCl, 2,6-lutidine,
CH2Cl2, 0 °C.
A) of 1 with an appropriate bromide or iodide or by
reductive amination (route B) of 1 with an appropriate
aldehyde or ketone. The overall yield of the amines (2)
was in the range of 60-80%; the reductive amination
route was always more high yielding. In the case of 2c,
its preparation was accomplished efficiently (92%) via the
Michael addition (MeOH, rt) of 1 to methyl acrylate. The
amines (2) were then converted to the acetoacetamides
(3a-h) by reaction with diketene in the presence of a
catalytic amount of DMAP. We found that a higher yield
of diazoacetoacetamides (4) was obtained if compounds
3 were not purified, but used directly in the diazotization
step with methanesulfonyl azide (MsN3). DBU was
preferred over Et3N as the base for these reactions. Good
yields (70-80%) of the diazoamides (4a-h) were ob-
tained.
Deacylation of compounds 4a,b,d-h was initially
accomplished by treating the diazo substrates with LiOH‚
H2O (3.5 molar equiv) in aqueous THF12a to afford
compounds 6a,b,d-h (60-75% yield). However, it was
found that longer reaction time resulted in further
hydrolysis of the desired product. An alternative de-
acylation procedure12b involving the use of 5% aqueous
KOH in acetonitrile was found to be milder, and afforded
higher yields (75-85%) of 6, although slightly longer
reaction times were required.
We now report the details9a of our studies on the use
of the N-BTMSM group as a N-protecting group in
rhodium(II) catalyzed reactions of diazoamides. We found
that the N-BTMSM group was effective as a conforma-
tional control element for the amide N-C(O) bond in
tertiary diazoamides. For N-CR-branched diazoamides,
the N-BTMSM group was also able to influence the
conformational preference about the amide N-CR moiety,
and this feature as well as electronic effects govern the
regioselectivity of the reaction.
Results and Discussion
For the preparation of the R-(carbomethoxy)-R-diazo-
acetamides (5a-g), the best route was the direct acyl-
ation of the secondary amines (2) with methyl diazo-
malonyl chloride.13 This provided 5a-g in yields ranging
from 70 to 85%. The traditional route involving conden-
sation of 2 with monomethyl malonic acid (DCC, cat.
DMAP) to obtain the corresponding R-(carbomethoxy)-
acetamides followed by diazo transfer (MsN3, DBU) gave
low overall yields. Although the amide formation step
proceeded uneventfully, the diazotization step was prob-
lematic; the reaction was plagued by long reaction times,
poor conversion and decomposition of both diazo product
and starting ester amide. The use of NaH as the base
The diazoamides were prepared by standard proce-
dures as outlined in Scheme 1. The secondary amines
(2) were prepared either via direct N-alkylation (route
(5) (a) Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.; Daniel,
K. L. Tetrahedron Lett. 1992, 33, 7819. (b) Clayden, J.; Tchabanenko,
K. Chem. Commun. 2000, 317.
(6) N-(4-Nitrophenyl): Anada, M.; Hashimoto, S.-i. Tetrahedron Lett.
1998, 39, 79. (b) N-(Carbalkoxyethyl): Yoon, C. H.; Zaworotko, M. J.;
Moulton, B.; Jung, K. W. Org. Lett. 2001, 3, 3539.
(7) (a) Wee, A. G. H.; Liu, B. S.; Zhang, L. J. Org. Chem. 1992, 57,
4404. (b) Wee, A. G. H.; Liu, B. S.; McLeod, D. D. J. Org. Chem. 1998,
63, 4218.
(8) Wee, A. G. H.; McLeod, D. D. Heterocycles 2000, 53, 637.
(9) (a) Preliminary communication: Wee, A. G. H.; Duncan, S. C.
Tetrahedron Lett. 2002, 43, 6173. (b) Doyle, M. P.; Hu, W.; Wee, A. G.
H.; Wang, Z.; Duncan, S. C. Org. Lett. 2003, 5, 407.
(10) Picard, J.-P. Can. J. Chem. 2000, 78, 1363. (b) Palomo, C.;
Aizpurua, J. M.; Ganboa, I.; Benito, A.; Cuerdo, L.; Fratila, R. M.;
Jimenez, A.; Loinaz, I.; Miranda, J. I.; Pytlewska, K. R.; Micle, A.;
Linden, A. Org. Lett. 2004, 6, 4443.
(12) (a) Bode, J. W.; Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L.
J. Org. Chem. 1996, 61, 9146. (b) Doyle, M. P.; Bagheri, V.; Wandless,
T. J.; Harn, N. K.; Brinker, D. A.; Eagle, C. T.; Loh, K.-L. J. Am. Chem.
Soc. 1990, 112, 1906.
(13) Marino, J. P.; Osterhout, M. H.; Price, A. T.; Sheehan, S. M.;
Padwa, A. Tetrahedron Lett. 1994, 35, 849.
(11) For a recent review on N-protecting groups: Theodoridis, G.
Tetrahedron 2000, 56, 2339.
J. Org. Chem, Vol. 70, No. 21, 2005 8373

Wee and Duncan
TABLE 1. Rh(II)-Catalyzed Reaction of 4-6(a,b): Regio-
products 7-9b. In the case of 6b (entry 8), moving the
phenyl unit farther by one methylene unit resulted in
the complete suppression of the undesired cycloaddition
pathway.
and Chemoselectivity
γ-lactam:
7, 8, or 9
yieldb
(%)
entry
diazoamide
catalysta
We next studied the Rh2(OAc)4-catalyzed reaction of
1
2
3
4
5
6
7
8
4a
5a
5a
6a
6a
4b
5b
6b
Rh2(OAc)4
Rh2(OAc)4
Rh2(Piv)4
Rh2(OAc)4
Rh2(cap)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
7a
8a
8a
9a
9a
7b
8b
9b
86
82
94
65c
75c
72
70
82
diazo compounds 4c and 5c (eq 2). It has been shown14
a Reactions were carried out using 2 mol % of Rh(II) catalyst in
refluxing CH2Cl2. b Isolated yield of chromatographically pure 7,
8, or 9. c Cycloheptatriene derivative 10 was also isolated. For
Rh2(OAc)4, 33%; for Rh2(acam)4, 22%.
that an electron-withdrawing carbalkoxy group deacti-
vates R and, to a lesser extent, â C-H bonds toward
metallocarbenoid insertion. We7a and others4b have also
shown that the Rh(II)-catalyzed reaction of diazoamides
possessing a N-(carboalkoxyethyl) substituent yielded
products that had arisen from metallocarbenoid insertion
into C-H bonds R and â to the carboalkoxy moiety and
from the carbonyl ylide derived from the interception of
the metallocarbenoid by the carbonyl oxygen of the ester
moiety.
For 4c and 5c, the Rh(II)-carbenoid C-H insertion
occurred exclusively at the electron-rich amide N-acti-
vated â-C-H bond to give 11 (71%) and 12 (82%) in very
good yields. Neither the γ-lactam nor the dihydro[1,4]-
oxazepin-3-one derivative, which would be formed via a
carbonyl ylide intermediate, was detected. Compound 11
was obtained only as the trans7a diastereomer whereas
12 was obtained as a 2:1 mixture of cis-7a and trans-
diastereomers. It is likely that in the case of 11, the
electron-withdrawing acetyl group caused the C-3 proton
to be more acidic which facilitated epimerization at C-3,
under the reaction conditions,15 to form the thermody-
namically more stable trans product.
and dry ether or dry DME as solvent, reaction conditions
that have been found7b to be effective in other systems,
did not alleviate the situation.
The Rh(II)-catalyzed reaction of the diazoamides 4-6a,b
(eq 1) was first examined to assess whether the N-
BTMSM group would be tolerated by the reactive Rh(II)-
carbenoid and to determine the regio- and chemoselec-
tivity of the reaction. The results are summarized in
Table 1.
The combined results from the reaction of 4a-c, 5a-
c, and 6a,b suggest that the N-BTMSM group has a
strong bias on the conformation about the amide N-C(O)
bond (Figure 1) that is also advantageous; the preferred
amide rotamer is 13′, which has the N-BTMSM group
and the amide carbonyl moiety positioned syn to each
other. This then places the reactive Rh(II)-carbenoid
center closer to the R group for a facile C-H insertion
reaction.
The reactions proceeded efficiently to give good overall,
isolated yields of the γ-lactam products 7, 8, or 9. With
5a, the use of Rh2(Piv)4 (Piv ) (Me)3CCO2- ligand) gave
a higher yield of 8a but provided the same regio- and
chemoselectivity achieved with Rh2(OAc)4 (compare en-
tries 2 and 3). No â-lactam products were detected in
these reactions. Although the N-BTMSM unit has a
methine C-H bond, we were pleased to find that it was
not attacked by the reactive metallocarbenoid, and this
is likely due to the steric shielding of the methine C-H
bond by both trimethylsilyl groups.
Similarly, there was no product arising from C-H
insertion into any of the six methyl groups of the two
trimethylsilyl moieties. For the lactams 7a and 8a, the
relative stereochemistry at C2-C3 was assigned as trans
on the basis of the vicinal coupling constant of 9 Hz.7a
Unlike 4a and 5a the Rh2(OAc)4-catalyzed reaction of
6a (entries 4 and 5) afforded a readily separable mixture
of the γ-lactam 9a and the cycloheptatriene derivative
10, and in a ratio of 2:1. With the more “electron-rich”
Rh2(Cap)4 (Cap ) caprolactamate ligand), 6a gave com-
pounds 9a and 10 in 97% yield, and with a modest
improvement on the chemoselectivity for γ-lactam forma-
tion; the ratio of 9a/10 was 3.3:1. In the reaction of the
homologous diazoamides 4-6b (entries 6-8) regio- and
chemoselectivity was excellent, which led only to γ-lactam
FIGURE 1. Preferred conformation about the N-BTMSM
amide unit.
To further define the scope and limitations of the
N-BTMSM diazoamides in intramolecular C-H insertion
reactions, we investigated structurally more varied N-
BTMSM diazoamides 4d-h, 5d,g, and 6d-h to deter-
mine steric, conformational, and electronic effects on
regio- and chemoselectivity. Specifically, compounds 4d,f,
(14) Stork, G.; Nakatani, K. Tetrahedron Lett. 1988, 29, 2283.
(15) Watanabe, N.; Anada, M.; Hashimoto, S.-i.; Ikegami, S. Synlett
1994, 1031.
8374 J. Org. Chem., Vol. 70, No. 21, 2005

Bis(trimethylsilyl)methyl Group as an Effective N-Protecting Group
TABLE 2. Rh(II)-Catalyzed Reaction of 4d-f, 5d, and
6d-f
TABLE 3. Rh(II)-Catalyzed Reaction of 4g-6g
combined
yieldb (%)
relative
relative yield (%)
entry diazoamide
catalysta
yieldc (%)
diazo-
combined
entry amide catalysta yieldb (%)
γ/â lactams
16e/20e
1
2
3
4
5
4g
4g
5g
6g
6g
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(acam)4
87
21f/24,h 21:79
21f/24,h 27:73
22f/25,h 25:75
23g/26, 100:0
23g/26, 100:0
72d,e
65
1
2
4d
4d
5d
5d
6d
6d
6e
6e
4f
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
Rh2(acam)4
87
14d/17d, 100:0
14d/17d, 100:0
15d/18d, 100:0
15d/18d, 100:0
16d/19d, 100:0
16d/19d, 100:0
64c
75
85
94
3
4
71c
94
a Reactions were carried out using 2 mol % of Rh(II) catalyst in
refluxing CH2Cl2. b Yield of chromatographically pure products.
c Relative yields were calculated based on weight ratio of isolated
γ-lactams (21-23) and â-lactams (24-26). d Starting material was
not recovered. e Each of the γ- and â-lactam products, 21, 22 and
24, 25, respectively, was obtained as an inseparable mixture of
diastereomers. f Due to the complexity of the 1H NMR spectra, the
ratio of the diastereomers was not determined. g The ratio of cis-
23/trans-23, based on the integration of the H-5 multiplet at δ
3.31-3.51 (cis) and δ3.05-3.24 (trans), was 1:1 for Rh2(OAc)4 and
1:3 for Rh2(acam)4. h Ratio of cis-24/trans-24 dastereomers was 1:4
and was based on the integration ratio of the H-3 singlet at δ 3.65
(cis) and δ 3.57 (trans). Ratio of cis-25/trans-25 was 1:2 and was
based on the integration ratio of the H-3 singlet at δ 3.57 (cis)
and δ 3.55 (trans).
5
6
71
7
98
68:32
53:47
8
88
9
78d
57c,d
72
14f/17f, 67:33e
14f/17f, 67:33e
16f/19f, 100:0
16f/19f, 100:0
10
11
12
4f
6f
6f
78
a Reactions were carried out using 2 mol % of Rh(II) catalyst in
refluxing CH2Cl2. b Yield of chromatographically pure products.
c With Rh2(acam)4, reaction was incomplete in this case and
product yield was based on recovered starting material. d γ-lactam
(14f) and â-lactam (17f) were obtained as inseparable mixtures
of diastereomers. The IR spectrum showed the characteristic
ν(CdO) for the â-lactam at 1741 cm-1 and for the γ-lactam at 1676
cm-1 e The ratio of 14f/17f was based on the integration of the
.
H-3 singlet at δ 3.55 (17f) and at δ 3.14, 3.15 (14f).
gested that regioselectivity was governed mainly by
electronic and not steric factors; that is, metallocarbenoid
attack occurred preferentially at the electron-rich tertiary
C-H bond and steric hindrance at the tertiary site
appears not to retard the insertion reaction. In compound
6e (entries 7 and 8) excellent regioselectivity was still
achieved; however, chemoselectivity became an issue.
Cyclopropanation of the phenyl moiety was competitive
with tertiary C-H insertion in both Rh2(OAc)4- and
Rh2(acam)4-catalyzed reactions, which resulted in the
formation of the γ-lactam 16e and the cycloheptatriene
derivative 20 in high overall yields. These results taken
together with the data from 6a (Table 1, entries 4 and 5)
suggest that the Rh(II)-carbenoid wherein the carbenoid
carbon is unsubstituted shows a propensity for attack on
the phenyl moiety. R-Substituted Rh(II)-carbenoids (Table
1, entries 1-3) do not exhibit this tendency. A reasonable
explanation for this is the metallocarbenoid derived from
6e (or 6a) is less hindered and when located in close
proximity (due to the conformational bias provided by the
N-BTMSM group, vide supra) to the phenyl moiety would
partake in facile cyclopropanation of the phenyl ring.
Interestingly, attempted reaction of the acetyl substituted
diazoamide 4e with Rh2(OAc)4 resulted in a complex
mixture of unidentifiable products, and with Rh2(acam)4,
4e was recovered (96%) unchanged even after 24 h in
refluxing dichloromethane.
5d, and 6d-f were designed to examine electronic effects
on Rh(II)-carbenoid insertion reaction between tertiary
and secondary C-H bonds and between tertiary C-H
bonds,16 respectively. Diazoamides 4-6g and 4h, 6h will
permit the assessment of electronic effects on metallo-
carbenoid insertion into secondary and amide N-activat-
ed, tertiary C-H bonds. Further, the outcome of the
Rh(II)-catalyzed reaction of these compounds should also
allow us to ascertain whether the N-BTMSM group has
any influence on the conformational preference about the
amide N-C(“alkyl”) σ bond, which may affect the regio-
selectivity of the C-H insertion reactions. The results
from the Rh(II)-catalyzed reaction of 4d,f, 5d, and 6d-f
(eq 3) are collected in Table 2.
In diazoamides 4f and 6f (entries 9-12, Table 2) the
corresponding Rh(II)-carbenoid can select between two
tertiary C-H bonds, one of which is activated by the
amide nitrogen. The reaction of 4f catalyzed by Rh2(OAc)4
(entry 9) gave metallocarbenoid insertion into both
tertiary C-H bonds to give an inseparable, diastereo-
meric mixture of compounds 14f and 17f in a 2:1 ratio.
Changing the catalyst to Rh2(acam)4 (entry 10) had no
effect on the regioselectivity of the reaction. The overall
yield was, however, modest (57%) due to incomplete
reaction even after a prolonged reaction time (>72 h),
and starting material (27%) was recovered. On the other
hand, the Rh2(OAc)4- and Rh2(acam)4-catalyzed reaction
of 6f (entries 11 and 12) gave the γ-lactam 14f as the
sole product. The â-lactam 17f, which could arise from
It is clear from Table 2 that the Rh2(OAc)4-catalyzed
reaction of compounds 4d-6d showed a high preference
for insertion into the electronically activated tertiary
C-H bond1a,16 to give only the γ-lactams 14d-16d
(entries 1, 3, and 5). γ-Lactam formation was also the
favored pathway with the more electron-rich, less reac-
tive Rh2(acam)4 (acam ) acetamidate ligand) as catalyst
(entries 2, 4, and 6). These results suggest that the nature
of the ligand on the Rh(II) catalyst had no influence on
the regioselectivity of the reaction. The fact that in all
three cases â-lactam products were not detected sug-
(16) Taber, D. F.; Ruckle, R. E., Jr. J. Am. Chem. Soc. 1986, 108,
7686.
J. Org. Chem, Vol. 70, No. 21, 2005 8375

Wee and Duncan
metallocarbenoid insertion into the amide N-activated
tertiary C-H bond, was not detected. It is evident that
when two competitive pathways for C-H insertion are
favorable, the R-substituent at the Rh(II)-carbenoid
center has a subtle, but decisive, influence on the
regioselectivity of the reaction.
The above C-H insertion results are also nicely
complemented by the data from the Rh(II)-catalyzed
reaction of compounds 4g-6g (eq 4), which are sum-
marized in Table 3.
FIGURE 2. γ-Lactams 21-23.
The reaction of 4g catalyzed by Rh2(OAc)4 and
Rh2(acam)4 led to diastereomeric mixtures of the γ-lactam
21 and the â-lactam 24 (entries 1 and 2). There was a
preference for Rh(II)-carbenoid insertion into the amide
N-activated tertiary C-H bond over the secondary C-H
bond, and the ratio of 24/21 was very similar in both
reaction systems and falls in the range 2.7-3.7:1. The
reaction of 5g (entry 3) catalyzed by Rh2(OAc)4, mirrored
the results obtained for 4g. In contrast to the results for
4g and 5g, the exposure of 6g to both Rh2(OAc)4 and
Rh2(acam)4 proceeded efficiently to give the γ-lactam 23
as the sole product, and as a mixture of cis- and trans-
diastereomers (entries 4 and 5). A 1:1 ratio of cis-23/
trans-23 was obtained for the Rh2(OAc)4-catalyzed reac-
tion whereas with Rh2(acam)4 the ratio of cis-23/trans-
23 was 1:3. This latter outcome indicated that the more
“electron-rich” Rh2(acam)4 catalyst promoted the forma-
tion of the trans-diastereomer. Neither the γ-lactam that
could arise from insertion into the CR-methyl C-H bond
nor the â-lactam 26 that could form from insertion into
the amide N-activated tertiary methine C-H bond was
detected. This result is the same as that observed for the
reaction of 6f (see Table 2, entries 11 and 12), wherein
γ-lactam formation is favored.
FIGURE 3. â-Lactams 24, 25, and 30.
as indicated by the chemical shift positions of the C5-
methyl doublet for 21 (cis, δ 1.02; trans, δ1.24) and 22
(cis, δ1.04; trans, δ1.21). Two doublets were observed, one
centered at δ 3.02 (J ) 6 Hz), which was attributed to
H-3 in the cis,trans- and cis,cis-diastereomers and the
second was centered at δ3.06 (J ) 12 Hz), which was due
to H-3 in the trans,trans- and trans,cis-diastereomers.
In 22, the H-3 doublet for the cis,trans- and cis,cis-
diastereomers appeared at δ3.20 (J ) 5.0 Hz) and for the
trans,trans- and trans,cis-diastereomers, the H-3 doublet
resonated at δ 3.21 (J ) 9.9 Hz).
In the case of the â-lactams (Figure 3), NOE experi-
ments were performed on compound 24. Irradiation of
the H-3 singlet at δ 3.65 caused a 2.9% NOE enhance-
ment of the resonance of the C4-methyl singlet at δ 1.38.
On the other hand, irradiation of the H-3 singlet at δ
3.57 only resulted in an enhancement (5%) of the signal
of the C1′-methylene unit of the C4-pentyl group, but not
the C4-methyl singlet at δ 1.25. From these results, it
was concluded that when the C4-methyl group was cis to
the H-3 (δ 3.65) it was deshielded whereas if it was trans
to the H-3 (δ 3.57) it was shielded.
On the basis of the diagnostic chemical shift relation-
ship of the C4-methyl and H-3 resonances observed for
24, the relative stereochemistry of C4-methyl group and
H-3 in compound 25 was assigned. Thus, in cis-25, the
H-3 singlet appeared at δ 3.57 and the C4-methyl singlet
occurred at δ 1.37, and in trans-25, the H-3 resonated at
δ 3.55 and C4-methyl singlet appeared at δ 1.24. These
results were also in accord with previous studies17 on
3,4,4-trisubstituted â-lactams 30, which reported that in
cis-30, the C4-methyl group resonated at lower field (δ
1.42) and in trans-30, the C4-methyl group appeared at
higher field (δ 1.29).
1
The H NMR spectra of the diastereomeric mixtures
of γ-lactams 21-23 (Figure 2), and the â-lactams 24 and
25 (Figure 3) were quite complex. NOE experiments
performed on the lactams 23 and â-lactam 24 revealed
some interesting structural information. For the γ-lactam
23, NOE results confirmed the assigned relative stereo-
chemistry of the C4-pentyl and C5-methyl substituents.
More importantly, the experiments also revealed that the
C5-methyl doublet and the H-5 multiplet in cis-23 and
trans-23 had very characteristic chemical shifts. In cis-
23, the C5-methyl doublet resonated at higher field,
centered at δ 1.01 whereas in trans-23, the C5-methyl
doublet resonated at δ 1.16. The H-5 multiplet in cis-23
appeared at lower field in the range δ 3.39-3.46 but in
trans-23, H-5 resonated at higher field at δ 3.14-3.21.
These chemical shifts and in particular the chemical shift
of the C5-methyl doublet was helpful in the analysis of
We then studied the Rh2(OAc)4-catalyzed reaction of
the geometrically more constrained diazoamides 4h and
6h (eq 5). Interestingly, a similar behavior of the met-
1
the H NMR spectra for 21 and 22.
In the γ-lactams 21 and 22 (Figure 2) all four dia-
stereomers were detected; the relative stereochemistry
of the C4-pentyl and C5-methyl groups are cis and trans
(17) Stork, G.; Szajewski, R. P. J. Am. Chem. Soc. 1974, 96, 5787.
8376 J. Org. Chem., Vol. 70, No. 21, 2005

Bis(trimethylsilyl)methyl Group as an Effective N-Protecting Group
allocarbenoid, as seen in the reactions of 4g-6g (Table
2), was observed.
It was found that the Rh(II)-carbenoid derived from
diazoacetamide 6h showed a propensity for insertion into
the secondary C-H bonds of the cyclohexyl unit to give
a 75% yield of a mixture of cis- and trans-27b. The ratio
of cis-27b/trans-27b was 1:1.3 and was based on the
integration of the H-7a (ddd) signals centered at δ 2.85
(trans) and at δ 3.33 (cis). The corresponding spiro
â-lactam 28b was not detected. In contrast, the diazo-
acetoacetamide 4h led to the formation of the readily
separable γ-lactam 27a and the spiro â-lactam 28a; the
ratio of 27a/28a was 1:3.3. Compound 27a was obtained
as an inseparable mixture of two diastereomers. The 1H
NMR spectrum of 27a showed very similar features to
the spectrum of 27b with respect to the H-7a (ddd)
resonances, which were observed at δ 2.82 (trans) and δ
3.40 (cis). The other salient features in the 1H NMR
spectrum were the H-3 doublets, one centered at δ 3.04
(J3,3a ) 11.9 Hz) and the second signal occurred at δ 3.28
(J3,3a ) 8.5 Hz), that showed large vicinal coupling
constants which suggested that the H-3 and H-3a hy-
drogens were trans related. On the basis of the 1H NMR
data, the two diastereomers were assigned the cis,cis-
27a and trans,trans-27a structures. The ratio of cis,cis-
27a/trans,trans-27a was 1:1.5 and was based on the
integration of the H-7a resonances.
The overall composite results indicate that if the
carbon (CR) directly adjacent to the amide nitrogen atom
is unbranched, γ-lactam formation is highly favored (4-
5a,b,d and 6a,b,d,e), but the regioselectivity is also
subject to the usual electronic effects of the substituent
(for example, eq 2, 4c,5c vs Table 2, 4d-6d). However,
for the CR branched systems (4f, 6f, 4g-6g, 4h, 6h), the
data suggest that the regioselectivity of the reaction is
strongly influenced by the conformational preference
about the N-CR σ bond and, to a lesser extent, the
electronic effects from the R-substituent at the metallo-
carbenoid carbon.
FIGURE 4. Transition-state conformers for formation of γ-
and â-lactams.
favored process. It is envisioned that C-H insertion
during γ-lactam formation proceeded via the “chairlike”
transition states (TS), TS-A and TS-A′. For â-lactam
formation, the five-membered, “envelope-like” transition
states, TS-B and TS-B′ are involved. The conformation
about the N-BTMSM σ bond in each set of the transition
states, TS-A, A′ and TS-B, B′, was drawn on the basis of
AM1 calculations performed on model N-BTMSM di-
azoamides.19
For C-H insertion to occur,20 the Rh(II)-carbenoid
bond was aligned parallel to the target C-H σ bond.20a
Insertion of the carbenoid center into the C-H bond is
believed to involve the overlap of the vacant p-orbital of
the carbenoid carbon and the C-H sigma bond.20b
The unbranched systems, 4-6a,b,d and 6e (Tables 1
and 2), led only to γ-lactam products. In the case of
4-6a,b, the results suggest that C-H insertion proceeds
preferentially via the energetically more stable TS-A (R
) H, R′ ) Ph or CH2Ph, R” ) H) because R′ occupies the
more stable pseudoequatorial position. TS-A′, is energeti-
cally less preferred due to the pseudoaxial orientation of
R′ and the developing 1,3-diaxial interaction between R′
and E (MeC(O) or CO2Me). For the diazoamides 4-6d
and 6e, insertion occurs preferentially at the tertiary
C-H bond,16 which has to involve only TS-A (R ) H, R′
) Me or Ph, R′′ ) Me) because in TS-A′, R′′ ) Me and
the target C-H bond is oriented away from the Rh(II)-
carbenoid carbon. The formation of the corresponding
â-lactam products, via TS-B and B′, is enthalpically less
favored due to developing ring and steric strain in these
transition states. However, in the case of diazoamides
4c,5c (eq 1) only the â-lactam products (11 and 12) were
(19) AM1 calculations (PC Spartan Pro 6.06) were performed on
model CR-unbranched and branched N-BTMSM diazoamides to deter-
mine the minimum energy conformation about the N-BTMSM σ bond.
For TS-A, A′, N-BTMSM,N-butyl-R-diazoacetamide was used: ∆Hf [syn
The formation of the γ- and â-lactams can be under-
stood by considering the four competing, rapidly inter-
convertible18 transition-state conformers A, A′, B, and B′
(Figure 4). γ-Lactam formation is, in general, a kinetically
(Me3Si)2CH/amide CdO]
(Me3Si)2CH/amide CdO]
)
)
-56.645 kcal mol-1 and ∆Hf [anti
-52.805 kcal mol-1
. For TS-B, B′,
N-BTMSM,N-(2-pentyl)-R-diazoacetamide was used: ∆Hf [syn
(18) A Curtin-Hammett scenario is considered here. â-and γ-Lactam
product ratios are determined by the difference in the transition state
energies (∆∆Gq) between A and A′ for γ-lactam formation, between B
and B′ for â-lactam formation and between TS-A, A′ and B, B′ in
reactions where both types of lactam products are formed. For a
discussion on the Curtin-Hammett principle, see: Seeman, J. I. Chem.
Rev. 1986, 86, 42.
(Me3Si)2CH/amide CdO]
(Me3Si)2CH/amide CdO] ) -53.717 kcal mol-1
)
-53.170 kcal mol-1 and ∆Hf [anti
.
(20) (a) Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc.
1996, 118, 547. (b) Doyle, M. P.; Westrum, L. J.; Wolthius, W. N. E.;
See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem.
Soc. 1993, 115, 958. (c) Nakamura, E.; Yoshikai, N.; Yamanaka. M. J.
Am. Chem. Soc. 2002, 124, 7181.
J. Org. Chem, Vol. 70, No. 21, 2005 8377

Wee and Duncan
obtained. This means that TS-A and A′, which leads to
the γ-lactam products, are energetically disfavored since
it requires Rh(II)-carbenoid insertion into an electroni-
cally deactivated C-H bond. The preferred reaction path-
way is via TS-B and B′, as it involves metallocarbenoid
insertion into the more electro-rich amide N-activated
C-H bond. This process is energetically favored because
of the increased electrophilicity7a of the R-acetyl- and
R-carbomethoxy-substituted Rh(II)-carbenoid carbon cen-
ters. The enhanced electrophilicity of these R-substituted
metallocarbenoids causes their interaction with the N-
activated C-H bond to occur at a greater distance; that
is, TS-B and B′ (R ) H, R′ ) CO2Me, R′′ ) H) may
represent earlier transition states (more open TS)7b along
the reaction coordinate. In this situation, any ring and
steric strain emanating from nonbonded interactions in
each of the transition states may not be as significant.
Further, diazoamide 5c gave a mixture of cis- and trans-
â-lactams 12, which lends further support for the in-
volvement of TS-B and B′ during â-lactam formation.
The Rh(II)-carbenoid derived from the diazoamides 4f,
6f, 4-6g, 4h, 6h (Tables 2 and 3, and eq 5) showed two
distinct behaviors. Note that the results obtained for the
reaction of the diazoacetamides 6g and 6h, and for the
R-substituted diazoacetamides 4g, 4h, and 5g are very
similar. Therefore, the discussions below will be confined
to the representative compounds 6g and 4g from each
group, respectively.
that early, more open transition states are involved. The
results suggest that C-H insertion proceeds through all
four transition states, TS-A, A′, B and B′ (E ) MeC(O),
CO2Me, R ) Me, R′ ) C5H11, R′′ ) H), resulting in the
formation of the observed â- and γ-lactam products.
For compound 4f, both γ-lactam (14f, major) and
â-lactam (17f, minor) products were obtained. This
outcome indicates that Rh(II)-carbenoid insertion into the
methine C-H (via TS-A, A′) and the amide N-activated
tertiary C-H (via TS-B, B′) bonds are competitive
wherein the former process is moderately favored. Also,
TS-B and B′ are now energetically easier to attain due
to their more open structures. A similar line of reasoning
can be applied to 4g (4h, 5g) except that the electrophilic
Rh(II)-carbenoid intermediate now shows a marked
preference for the more nucleophilic amide N-activated
tertiary C-H (TS-B, B′) over the secondary methylene
C-H16 (TS-A, A′) bonds, resulting in the formation of the
â-lactam (24) as the major product. It was also found that
the trans-â-lactam was favored over the cis-diastereomer
in the reaction of 4g (5g), and this outcome can be
rationalized by consideration of TS-B and B′ (E )
MeC(O), R ) Me, R′ ) C5H11, R′′ ) H). In TS-B, a syn-
methyl/acetyl interaction is present, but this steric
interaction is not as severe as the syn-CH2C5H11/acetyl
interaction present in TS-B′. Consequently, TS-B′ is
relatively more destabilized and C-H insertion prefers
to occur via TS-B to give the trans-â-lactam.
The diazoacetamides 6f, 6g (6h) have an amide N-
activated, tertiary C-H bond, but Rh(II)-carbenoid
insertion is seen to occur at the methine (6f, TS: R ) R′
) R′′ ) Me) and methylene (6g, TS: R ) Me, R′ ) C5H11,
R′′ ) H) C-H bonds to give only the γ-lactams. The
Rh(II)-carbenoid intermediate derived from 6f,g is less
electrophilic (compared to the R-substituted metallocar-
benoids), and therefore, effective interaction with the
target C-H bond will require a closer approach of the
metallocarbenoid to the C-H bond. This leads to a later
transition state that is more compact.7b The involvement
of a more compact transition state means that TS-B and
B′ have inherently higher energies (severe ring strain
and nonbonded interactions) than TS-A and A′. There-
fore, the reaction proceeds preferentially via the rela-
tively more stable TS-A and A′18 to give only the γ-lactam
products (16 and 23). Further, in the case of 6g, the
diastereoselectivity of the C-H insertion reaction was
found to be higher with Rh2(acam)4 (cis-23/trans-23; 1:3)
than with Rh2(OAc)4 (cis-23/trans-23; 1:1) as catalysts.
A reasonable explanation for the higher diastereoselec-
tivity in the Rh2(acam)4-catalyzed reaction is that the
corresponding Rh(II)-carbenoid is much less electrophilic
than the Rh2(OAc)4-carbenoid, which means that TS-A
and A′ are even more compact in the Rh2(acam)4-
catalyzed reaction. In TS-A′ (E ) H, R ) Me, R′ ) C5H11,
R′′ ) H), a severe 1,3-diaxial interaction between the
C5H11 (R′) unit and the hydrogen moiety in the carbenoid
carbon destabilizes this transition state over TS-A,
wherein the C5H11 unit occupies the pseudoequatorial
position. Preferential reaction via the lower energy TS-
A18 results in a higher ratio of trans-23.
Conclusions
In conclusion, the effectiveness of the N-bis(trimethyl-
silyl)methyl group for conformational control about the
amide N-C(O) bond in tertiary diazoamides was dem-
onstrated. In CR-unbranched diazoamides, the regio-
selectivity of the C-H insertion reaction was influenced
by the inherent electronic effects of the N-“alkyl” group,
whereas in CR-branched systems regioselectivity was
governed by conformational preference about the amide
N-CR bond as well as by subtle, but important electronic
effects of the R-substituent at the carbenoid carbon. A
transition state model is proposed to rationalize the
regioselectivity of the C-H insertion reaction of the
N-BTMSM diazoamides. Further studies are directed at
expanding the use of N-BTMSM diazoamides in the
synthesis of N-heterocycles, such as trisubstituted γ-lac-
tams and tetrahydro-â-carbolines.
Experimental Section
General Procedure for Rhodium(II)-Catalyzed Reac-
tions. The appropriate catalyst (2 mol %) in dry CH2Cl2 (3
mL) was refluxed at 45 °C under argon. A solution of the
appropriate diazo compound in dry CH2Cl2 (2 mL) was added
via cannula to the refluxing solution. The progress of the
reaction was monitored by TLC. After the reaction was
complete, the reaction mixture was cooled to rt and concen-
trated in vacuo and the residue purified by flash chromatog-
raphy.
1-[Bis(trimethylsilyl)methyl]-3-acetyl-4-phenyl-2-pyr-
rolidinone (7a). IR νmax (neat): 3030, 1717, 1667 cm-1 1H
.
NMR (200 MHz) δ: 0.10 (s, 18H), 2.42 (s, 1H), 3.01-3.17 (bs,
1H), 3.38 (dd, 1H, J ) 7.2, 11.2 Hz), 3.74 (d, 1H, J ) 7.2 Hz),
3.69-3.91 (m, 1H), 4.80 (dd, 1H, J ) 7.2, 15.2 Hz), 7.05-7.45
(m, 5H). 13C NMR (50.3 MHz) δ: 0.04, 30.7, 37.1, 38.3, 55.6,
62.6, 127.2, 127.3, 128.4, 141.3, 167.6, 203.4.
The reaction of the R-acetyl- and R-carbomethoxy-
diazoacetamides 4f-h and 5g produced â- and γ-lactam
products. The Rh(II)-carbenoid derived from these com-
pounds are more electrophilic (vide supra), which means
8378 J. Org. Chem., Vol. 70, No. 21, 2005

Bis(trimethylsilyl)methyl Group as an Effective N-Protecting Group
1-[Bis(trimethylsilyl)methyl]-3-methoxycarbonyl-4- 22.6, 28.4, 29.6, 32.8, 36.8, 62.0, 65.7, 169.3, 205.7. HRMS:
phenyl-2-pyrrolidinone (8a). IR νmax
:
3030, 1742, 1633
calcd for C14H28NO2Si2 (M - 15) 298.1658, found 298.1660.
1-Bis(trimethylsilyl)methyl-3-acetyl-4,4,5-trimethyl-2-
pyrrolidinone (14f) and 1-[Bis(trimethylsilyl)methyl]-3-
cm-1. 1H NMR (200 MHz) δ: 0.10 (s, 18H), 2.90-3.12 (bs, 1H),
3.45 (dd, 1H, J ) 8.4, 10.1 Hz), 3.65 (d, 1H, J ) 9.1 Hz), 3.68-
3.86 (m, 1H), 3.80 (s, 3H), 4.0 (dd, 1H, J ) 8.4, 16.9), 7.45-
7.10 (m, 5H). 13C NMR (50.3 MHz) δ: 0.05, 37.5, 41.5, 52.5,
55.1, 55.5, 126.0, 127.5, 128.3, 140.0, 167.3, 170.16. HRMS:
calcd for C18H28NO3Si2 (M - 15) 362.1607, found 362.1598.
acetyl-4-isopropyl-4-methyl-2-azetidinone (17f). IR νmax
:
1
1741, 1710, 1676 cm-1. H NMR (300 MHz) δ (mixture of γ-
and â-lactam diastereomers): 0.08, 0.10, 0.13, 0.14, 0.15 (s,
18H), 0.98 (d, J ) 6.5 Hz), 1.01 (d, J ) 6.7 Hz), 1.04 (d, J )
6.5 Hz), 1.05 (s), 1.09 (s), 1.16 (d, J ) 6.7 Hz),1.21 (s) and 1.22
(s) (9H), 1.76 (s), 1.94 (s) and 1.98 (s) (1H), 1.80-2.00 (m, 1H),
2.19 (s) and 2.28 (s) (3H), 3.14 (s) and 3.15 (s) (1H), 3.17 (q, J
) 6.7 Hz) and 3.52 (q, J ) 6.7 Hz) (1H), 3.55 (s, 1H). HRMS:
calcd for C15H30NO2Si2 (M - 15) 312.1815, found 312.1782.
1-[Bis(trimethylsilyl)methyl]-3-methoxycarbonyl-4,4-
1-[Bis(trimethylsilyl)methyl]-4-phenyl-2-pyrrolidi-
none (9a). Mp: 66.8-68.4 °C. IR νmax (CDCl3): 3038, 1661,
1604 cm-1. 1H NMR (200 MHz) δ: 0.10 (d, 18H), 2.66 (dd, 1H,
J ) 8.8, 16.4 Hz), 2.78 (dd, 1H, J ) 8.8, 16.4 Hz), 3.10-3.24
(bs, 1H), 3.32-3.60 (m, 1H), 3.44 (dd, 1H, J ) 7.8, 15.9 Hz),
3.70 (dd, 1H, J ) 7.8, 15.9 Hz), 7.05-7.45 (m, 5H). 13C NMR
(50.3 MHz) δ: 0.0, 35.3, 37.6, 37.9, 55.9, 125.5, 125.9, 128.89,
142.0, 172.1. HRMS: calcd for C17H29NOSi2 (M+) 319.1778,
found 319.1783.
dimethyl-2-pyrrolidinone (15d). IR νmax: 1736, 1677 cm-1
.
1H NMR (200 MHz) δ: 0.13 (s, 18H), 1.08 (s, 3H), 1.21 (s, 3H),
1.90 (s, 1H), 3.03 (s, 1H), 3.04 (d, 1H, J ) 9.6 Hz), 3.41 (d, 1H,
J ) 9.6 Hz), 3.70 (s, 3H). 13C NMR (50.3 MHz) δ: 0.3, 23.1,
29.7, 36.4, 51.8, 60.0, 62.0, 168.5, 170.0. HRMS: calcd for
C14H28NO3Si2 (M - 15) 314.1607, found 314.1608.
1-[Bis(trimethylsilyl)methyl]-3-acetyl-4-benzyl-2-pyr-
rolidinone (7b). IR νmax: 3023, 1713, 1658 cm-1 1H NMR
.
(200 MHz) δ: 0.10 (s, 18H), 2.69-2.79 (m, 2H), 2.99-3.25 (m,
3H), 3.33 (d, 1H, J ) 4.4 Hz), 3.41-3.58 (m, 1H), 7.00-7.40
(m, 5H). 13C NMR (50.3 MHz) δ: 0.03, 30.2, 34.5, 37.1, 38.99,
53.5, 61.0, 126.7, 128.7, 128.8, 138.5, 166.8, 204.2. HRMS:
calcd for C20H33NO2Si2 (M+) 375.2050, found 375.2053.
1-[Bis(trimethylsilyl)methyl]-4,4-dimethyl-2-pyrrolidi-
none (16d). Mp: 54.7-55.3 °C. IR νmax: 1654 cm-1. 1H NMR
(200 MHz) δ: 0.08 (s, 18H), 1.13 (s, 6H), 2.06 (s, 1H), 2.20 (s,
2H), 3.12 (s, 2H). 13C NMR (50.3 MHz) δ: 0.1, 28.3, 32.3, 35.1,
45.5, 62.8, 172.7. HRMS: calcd for C13H29NOSi2 (M+) 271.1788,
found 271.1781.
1-[Bis(trimethylsilyl)methyl]-4-methyl-4-phenyl-2-pyr-
rolidinone (16e). IR νmax: 3050, 1672, 1588 cm-1. 1H NMR δ
(300 MHz): 0.15 and 0.05 (s, 18H), 1.50 (s, 3H), 2.55 (d, 1H, J
) 15.9 Hz), 2.86 (d, 1H, J ) 15.9 Hz), 3.15 (bs, 1H), 3.51 (d,
1H, J ) 9.6 Hz), 3.70 (d, 1H, J ) 9.6 Hz), 7.10-7.20 (m, 5H).
13C NMR (75.5 MHz) δ: 0.2, 0.3, 30.2, 36.7, 40.2, 44.5, 62.5,
125.4, 126.6, 128.7, 147.1, 172.2. HRMS: calcd for C17H28NOSi2
318.1709 (M+ - 15), found 318.1708.
1-[Bis(trimethylsilyl)methyl]-4,4-dimethyl-5-methyl-2-
pyrrolidinone (16f). IR νmax: 1677 cm-1. 1H NMR (200 MHz)
δ: 0.10 (s, 18H), 0.81 (s, 3H), 1.05 (d, 3H, J ) 6.2 Hz), 1.13 (s,
3H), 1.98 (s, 1H), 2.03 (d, 1H, J ) 16.0 Hz), 2.16 (d, 1H, J )
16.0 Hz), 3.17 (q, 1H, J ) 6.2 Hz). 13C NMR (50.3 MHz) δ: 0.5,
1.0, 14.1, 23.2, 28.5, 38.8, 44.9, 66.2, 172.5. HRMS: calcd for
C14H31NOSi2 (M+) 285.1944, found 285.1938.
1-[Bis(trimethylsilyl)methyl]-3-methoxycarbonyl-4-
benzyl-2-pyrrolidinone (8b). IR νmax: 3027, 1742, 1683 cm-1
.
1H NMR (200 MHz) δ: 0.10 (s, 18H), 2.78 (d, 2H, J ) 7.3 Hz),
2.94-3.17 (m, 3H), 3.21 (d, 1H, J ) 6.9 Hz), 3.49 (dd, 1H, J )
7.3, 9.1 Hz), 3.63 (s, 3H), 7.05-7.40 (m, 5H). 13C NMR (50.3
MHz) δ: 0.20, 37.9, 39.9, 52.7, 54.1, 89.8, 126.9, 128.8, 129.0,
138.3, 167.8, 171.0. HRMS: calcd for C20H33NO3Si2 (M - 15)
376.1764, found 376.1765.
1-[Bis(trimethylsilyl)methyl]-4-benzyl-2-pyrrolidi-
none (9b). Mp: 69.3-71.8 °C. IR νmax: 3065, 1657 cm-1. H
1
NMR (200 MHz) δ: 0.10 (s, 18H), 2.19 (dd, 1H, J ) 5.8, 16.1
Hz), 2.40-2.80 (m, 4H), 3.08 (bs, 1H), 3.15 (dd, 1H, J ) 5.1,
9.9 Hz), 3.42 (dd, 1H, J ) 6.9, 9.8 Hz), 7.05-7.40 (m, 5H). 13
C
NMR (50.3 MHz) δ: 0.04, 33.2, 36.5, 40.8, 54.7, 90.0, 126.5,
128.6, 128.7, 139.1, 172.4. HRMS: calcd for C17H28NOSi2 (M
- 15) 318.1709, found 318.1710.
2-[Bis(trimethylsilyl)methyl]-2,3,4,9a-tetrahydro-1H-
cyclohepta[c]pyridin-1-one (10). IR νmax: 3026, 1633, 1622
cm-1. 1H NMR (200 MHz) δ: 0.10 (s, 18H), 2.40-2.72 (m, 3H),
3.20-3.62 (m, 2H), 4.30-4.10 (bs, 1H), 5.39 (dd, 1H, J ) 5.1,
9.0 Hz), 5.99-6.04 (bs, 1H), 6.08-6.27 (m, 1H), 6.42-6.63 (m,
2H). 13C NMR (50.3 MHz) δ: 0.12, 30.9, 39.1, 45.5, 47.8, 118.4,
120.3, 122.4, 125.7, 129.8, 130.1, 132.8, 168.4. HRMS: calcd
for C17H29NOSi2 (M+) 319.1788, found 319.1783.
2-[Bis(trimethylsilyl)methyl]-4-methyl-3,4-dihydro-2H-
cyclohepta[c]pyridin-1(9aH)-one (20). IR νmax: 3023, 1637
1
cm-1. H NMR δ (300 MHz) δ: 0.10 (s, 18H), 1.12 (d, 3H, J )
6.9 Hz), 2.76-2.88 (m, 1H), 3.16 (dd, 1H, J ) 12.4, 7.4 Hz),
3.28-3.55 (m, 2H), 2.50 and 4.18 (bs, 1H), 5.20-5.30 (m, 1H),
5.99-6.03 (m, 1H), 6.18-6.25 (m, 1H), 6.55-6.60 (m, 2H). 13
C
NMR (75.5 MHz) δ: 0.5, 18.3, 35.2, 45.9, 50.0, 55.0, 59.8, 119.0,
121.3, 126.1, 130.0, 131.2, 139.1 (CdO not observed). HRMS:
calcd for C17H28NOSi2 (M+ - 15) 318.1709, found 318.1718.
3-Acetyl-1-[bis(trimethylsilyl)]methyl-5-methyl-4-pen-
tyl-2-pyrrolidinone (21). IR νmax: 1717, 1676 cm-1. 1H NMR
(300 MHz, mixture of four diastereomers) δ: 0.09, 0.11 and
0.12 (s, 18H), 1.04 and 1.21 (d, 3H, J ) 7.5 Hz), 1.22-1.60 (m,
9H), 1.93-2.20 (br s, 1H), 2.35 and 2.38 (s, 3H), 2.86 (dddd,
0.2H, 7.1, 7.1, 7.1, 7.1, 10.7 Hz), 3.06-3.16 (m, 0.6H) and 3.47
(quint, 0.2H, J ) 7.1 Hz) (H-5), 3.20 (d, J ) 5.0 Hz) and 3.21
(d, J ) 9.9 Hz) (1H, H-3).
1-[Bis(trimethylsilyl)methyl]-3-acetyl-4-(methoxycar-
bonylmethyl)-2-azetidinone (11). IR νmax: 1741, 1713, 1641
1
cm-1. H NMR (200 MHz) δ: 0.10 (s, 18H), 2.05 (s, 1H), 2.27
(s, 3H), 2.48 (dd, J ) 7.9, 16.7 Hz), 2.74 (dd, 1H, J ) 6.5, 16.7
Hz), 3.93 (s, 3H), 3.93 (d, 1H, J ) 2.0 Hz), 4.30-4.14 (m, 1H).
13C NMR (50.3 MHz) δ: -0.1, -0.2, 30.1, 35.5, 38.6, 51.6, 52.1,
67.1, 161.7, 170.4, 200.1. HRMS: calcd for C14H26NO4Si2 (M
- 15) 328.1400, found 328.1413.
1-[Bis(trimethylsilyl)methyl]-3-methoxycarbonyl-4-
(methoxycarbonylmethyl)-2-azetidinone (12). IR νmax
:
1-[Bis(trimethylsilyl)methyl]-3-carbomethoxy-5-meth-
1738, 1689, 1625 cm-1. 1H NMR (200 MHz) δ (cis diastereomer
in brackets): 0.10 (s, 18H), 2.10 (s, 1H), 2.50 (dd, J ) 8.2, 16.1
Hz), 2.90-2.65 (m, 1H), 3.65 (d, J ) 2.0 Hz) and [3.69 (d, J )
5.1 Hz)] (1H), 3.70 (s, 3H), 3.75 (s, 3H), 3.95-4.15 (m, 1H).
13C NMR (50.3 MHz) δ (cis diastereomer in brackets): -0.3,
-2.0, 33.3, 35.6, 36.4, (52.5), 52.6, 53.7, 6.32, 59.0, 167.8, 170.2,
170.9. HRMS: calcd for C15H29NO5Si2 (M+) 359.1583, found
359.1587.
yl-4-pentyl-2-pyrrolidinone (22). IR νmax: 1743, 1683 cm-1
.
1H NMR (300 MHz, mixture of four diastereomers) δ: 0.09,
0.11 and 0.14 (s, 18H), 1.02 and 1.24 (d, 3H, J ) 6.3 Hz), 1.12-
1.60 (m, 9H), 1.93-1.98 (br s, 1H), 2.18 (dddd, J ) 6.3, 6.3,
6.3, 8.4 Hz), 2.76 (dddd, J ) 8.4, 8.4, 8.4, 11.4 Hz), 3.08 (quint,
J ) 7.3 Hz) and 3.41 (quint, J ) 7.3 Hz) (1H), 3.02 (d, J ) 6
Hz) and 3.06 (d, J ) 12 Hz), 3.68, 3.74 and 3.75 (s, 3H).
HRMS: calcd for C18H36NO2Si2 (M - 15) 370.2234, found
370.2237.
1-Bis(trimethylsilyl)methyl-3-acetyl-4,4-dimethyl-2-
pyrrolidinone (14d). Mp: 54.8-56.7 °C. IR νmax: 1715, 1677
1-Bis(trimethylsilyl)methyl-5-methyl-4-pentyl-2-pyr-
1
1
cm-1. H NMR (200 MHz) δ: 0.01 (s, 18H), 1.10 (s, 3H), 1.24
rolidinone (23). IR νmax: 1735, 1678 cm-1. H NMR δ (200
(s, 3H), 1.88 (s, 1H), 2.28 (s, 3H), 3.0 (d, 1H, J ) 8.9 Hz), 3.20
MHz, cis-diastereomer in square brackets): 0.88 (t, 3H, J )
6.1 Hz), 0.10 (m, 18H), [1.10 (d, J ) 6.7 Hz)] and 1.15 (d, 3H,
(s, 1H), 3.40 (d, 1H, J ) 8.9 Hz). 13C NMR (50.3 MHz) δ: 0.2,
J. Org. Chem, Vol. 70, No. 21, 2005 8379

Wee and Duncan
J ) 6.5 Hz) (3H), 1.20-1.51 (m, 8H), 1.68-2.36 (m, 3H), 2.49
(dd, 1H, J ) 8.8, 16.7 Hz), 3.05-3.24 and [3.31-3.51] (m, 1H).
13C NMR (50.3 MHz) δ: 0.6, 0.8, [13.0] 13.1, 19.3, [21.9] 22.5,
25.6, [27.2] 27.6, (29.6), 29.9, [31.7] 31.7, [35.0] 35.5, [36.2] 36.5,
37.6, 40.3, 6.79, 172.7. HRMS: calcd for C16H34NOSi2 (M -
15) 312.2179, found 312.2163. 1H NMR δ (500 MHz, cis-
diastereomer in square brackets): 0.01 (m, 18H), 0.88 (t, 3H,
J ) 6.6 Hz), [1.01 (d, J ) 6.7 Hz)] and 1.16 (d, J ) 6.4 Hz)
(3H), 1.22-1.36 (m, 8H), 1.91-2.08 (m, 2H), 2.25-2.40 (m, 1H),
2.52 (dd, 1H, J ) 8.7, 16.8 Hz), 3.14-3.21 and [3.39-3.46] (m,
1H).
NOE Data (500 MHz) for cis-23 and trans-23. cis-23.
Irradiation of H-5 (quintet, δ 3.42) resulted in a 3.7% enhance-
ment of the H-4 multiplet (δ 2.00-2.08). When C5-Me (d, δ
1.95) was irradiated, there was no NOE effect observed for
H-4. trans-23. Irradiation of the H-5 quintet (δ 3.18) gave a
small NOE at H-4 (m, δ 1.84-1.75) of 0.6%; however irradia-
tion of C5-Me doublet (δ 1.99) produced a 3.7% NOE of the
H-4 sigmal.
1.12-1.87 (m, 10H), 1.94 (s, 1H), 3.55 and 3.57 (s, 1H), 3.70
and 3.73 (s, 3H). 13C NMR (50.3 MHz) δ: 0.4, 0.5, 14.0, 18.0,
[22.5] 22.5, 23.6, [24.9] 25.4, [29.5] 29.7, 31.6, 34.4, 35.3, 40.1,
52.0, [61.1] 61.9, 161.4, 168.3. HRMS: calcd for C19H39NO3Si2
(M+) 385.2468, found 385.2476.
3-Acetyl-1-[bis(trimethylsilyl)methyl]hexahydro-1H-
indol-2(3H)-one (27a). IR νmax: 1684, 1708 cm-1 1H NMR
.
(300 MHz) δ (mixture of cis/trans diastereomers): 0.05, 0.07,
0.08, 0.10, 0.13 (s, 18H), 1.16-1.96 (m, 9H), 2.00-2.13 (m) and
2.88-2.95 (m) (1H), 2.34 and 2.38 (s, 3H), 2.82 (ddd, J ) 10.2,
10.2, 3.4 Hz) and 3.40 (ddd, J ) 8.5, 6.8, 5.1 Hz) (1H), 3.04 (d,
J ) 11.9 Hz) and 3.28 (d, J ) 8.5 Hz) (1H). HRMS: calcd for
C17H33NO2Si2 339.2049, found 339.2046. HRMS: calcd for
C16H30NO2Si2 (M - 15) 324.1815, found 324.1815.
1-[Bis(trimethylsilyl)methyl]hexahydro-1H-indol-2(3H)-
one (27b). IR νmax: 1684 cm-1. 1H NMR (300 MHz) δ (mixture
of cis/trans diastereomers): 0.08, 0.09, 0.12, 0.14 (s, 18H),
1.10-2.08 (m, 9H), 2.19 (dd, 1H, J ) 15.5, 6.9 Hz), 2.27 (dd,
1H, J ) 15.5 Hz, 6.9 Hz), 2.30-2.45 (m) and 2.89-2.97 (m)
(1H), 2.85 (ddd, J ) 9.8, 8.3, 2.4 Hz) and 3.33 (ddd, J ) 6.3,
4.9, 4.9 Hz) (1H). HRMS: calcd for C15H31NOSi2 297.1944,
found 297.1941. HRMS: calcd for C14H28NOSi2 (M - 15)
282.1709, found 282.1707.
1-[Bis(trimethylsilyl)methyl]-3-acetyl-1-azaspiro[3,5]-
nonan-2-one (28a). IR νmax: 1737, 1708 cm-1. 1H NMR (200
MHz) δ: 0.14 (s, 18H), 0.95-2.15 (m, 11H), 2.31 (s, 3H), 3.65
(s, 1H, H-3). 13C NMR (50.3 MHz) δ: 0.4, 0.6, 23.7, 24.4, 24.6,
30.2, 32.2, 43.6, 35.9, 67.7, 203.1. HRMS: calcd for C16H30-
NO2Si2 (M - 15) 324.1815, found 324.1805.
1-[Bis(trimethylsilyl)methyl]-3-acetyl-4-(1-methylhep-
1
tyl)-2-azetidinone (24). IR νmax: 1742, 1711 cm-1. H NMR
(200 MHz) δ (mixture of cis/trans diastereomers): 0.15 (s,
18H), 0.88 (t, 3H, J ) 6.1 Hz), 1.25 and 1.38 (s, 3H), 1.08-
1.50 (m, 10H), 1.98 (s, 1H), 2.30 (s, 3H), 3.57 and 3.65 (s, 1H).
1H NMR δ (500 MHz, mixture of cis/trans diastereomers): 0.17,
0.18, 0.19, 0.20 (s, 18H), 0.89 (t, 3H, J ) 7.3 Hz), 1.25 and
1.36 (s, 3H), 1.26-1.42 (m, 10H), 1.98 (s, 1H), 2.29 (s, 3H),
3.57 and 3.65 (s, 1H). 13C NMR (50.3 MHz) δ: 0.5, 0.6, 14.0,
19.2, 22.5, 23.5, (25.3), 25.7, (29.5), 29.7, (30.9), 31.6, (35.0),
35.4, 40.3, 63.1, 67.4, 68.5, 163.0, 202.5. HRMS: calcd for
C18H36NO2Si2 (M - 15) 354.2285, found 354.2265.
Acknowledgment. We thank the Natural Sciences
and Engineering Research Council, Canada, and the
University of Regina for financial support.
Supporting Information Available: Analytical and spec-
tral characterization of compound 4a-h, 5a-d,g and 6a,b,d-
h; 1H NMR spectra for compounds 4a-h, 5a-d,g, 6a,b,d-h,
7-9a,b, 10-12, 14d, 14f(17f), 15d, 16d-f, 20-25, 27a,b, and
28b; and 13C NMR spectra for 5g, 10, and 25. This material is
available free of charge via the Internet at http://pubs.acs.org.
1-[Bis(trimethylsilyl)methyl]-3-methoxycarbonyl-4-(1-
methylheptyl)-2-azetidinone (25). IR νmax: 1753, 1731 cm-1
.
1H NMR (200 MHz) δ (mixture of cis/trans-diastereomers):
0.20 (s, 18H), 0.87 (t, 3H, J ) 6.7 Hz), 1.24 and 1.37 (s, 3H),
JO051042E
8380 J. Org. Chem., Vol. 70, No. 21, 2005