Cross-metathesis of α-methylene-β-lactams: the first tetrasubstituted alkenes by CM

Article abstract of DOI:10.1016/j.tetlet.2008.12.060

α-Alkylidene-β-lactams have been prepared in good to excellent yields by olefin cross-metathesis. Electron-poor α-methylene-β-lactams undergo cross-metathesis more rapidly and efficiently than more electron-rich analogs. Significantly, tetrasubstituted al

Full text of DOI:10.1016/j.tetlet.2008.12.060

Tetrahedron Letters 50 (2009) 1020–1022
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cross-metathesis of
alkenes by CM
a-methylene-b-lactams: the first tetrasubstituted
*
Yanke Liang, Ravinder Raju, Tri Le, Christopher D. Taylor, Amy R. Howell
Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Alkylidene-b-lactams have been prepared in good to excellent yields by olefin cross-metathesis. Elec-
Received 6 December 2008
Accepted 11 December 2008
Available online 24 December 2008
tron-poor -methylene-b-lactams undergo cross-metathesis more rapidly and efficiently than more elec-
tron-rich analogs. Significantly, tetrasubstituted alkenes have for the first time been accessed by CM
reactions.
a
Ó 2008 Elsevier Ltd. All rights reserved.
a
-Alkylidene-b-lactams are structural units found in several po-
R
R
tent b-lactamase inhibitors.1 Moreover, they serve as building
blocks for the preparation of b-lactam antibiotics,2 as well as
b-amino alcohols and acids.3 A recent investigation in our group
demonstrated that cross-metathesis (CM)4 is an efficient and
O
O
1 or 2 (5 mol%)
CH2Cl2, reflux
12 - 24 h
R'
R'
O
O
n = 1, 2
55-94%
powerful tool to introduce various functional groups to
b-lactones (Scheme 1).5 It was anticipated that
-methylene-b-lac-
tams would exhibit similar reactivity. We herein describe our CM
results with -methylene-b-lactams, examining specifically the ef-
fect of substitution on the amide nitrogen. In addition, CM to give
tetrasubstituted alkenes is reported for the first time.
a-methylene-
Z:E >20:1-5:1
a
MesN NMes
MesN NMes
Cl
Cl
Ru
Cl
Ru
Cl
a
Ph
PCy3
iPr-O
1
2
Preliminary studies involved reactions between
a-methylene-
b-lactam 3 and terminal olefins a–c (2 equiv) in the presence of
Grubbs second generation catalyst 1 or the Grubbs-Hoveyda cata-
lyst 2 (Table 1, entries 1, 7, 8, 14, and 15). Coupling of 3 with 1-pen-
tene (a) was complete within 1 h using 2 mol % of 1 (entry 1).
Coupling with b, however, was only marginally promoted by 1,
while portion-wise additions of catalyst 2 gave a remarkable in-
crease in yield (entries 7 and 8). Catalyst 1 did not promote the
coupling of 3 with c; however, catalyst 2 did (entries 14 and 15).
Overall, with less reactive cross-partners (b and c), 2 appeared to
be more effective, and optimal yields were realized with portion-
wise additions.
Scheme 1. CM reactions of a-methylene-b-lactones.
entries 7–20). The lactams (entries 8–12) were subjected to identi-
cal reaction conditions, and the yields for lactams 3b and 4b were
the same. However, a notable decrease in yield was observed for
more electron-rich lactams, 5–7. The yield of 7b could be improved
from 57% (entry 12) to 72% with increased catalyst loading (entry
13).
For cross-partners, a and b, the initial charge of catalyst 2 usu-
ally led to the greatest conversion, but this barely promoted CM
reactions between allyl chloride (c) and lactams 3–7. In all cases,
the addition of a 5 mol % portion of 2 with heating for 12 h led to
considerable conversions, and an additional 1 mol % of 2 with con-
tinued heating for 1 h provided lactams 3c, 5c, 6c, and 7c in rea-
sonable yields (Table 1, entries 15, and 18–20). Although only
25% yield of 4c was obtained by using the same protocol (entry
16), portion-wise addition of 2 over the course of 3 h resulted in
the formation of 4c in an improved 60% yield (entry 17). However,
reactions with c were incomplete in all cases, and increasing the
catalyst loading did not improve the yields.
In order to determine whether the conclusions with 3 could be
extrapolated to other
a-methylene-b-lactams, we examined the
series 3–7. The reactivity of electron-poor lactam 3 was compared
to more electron-rich lactams 4–7. All lactams coupled efficiently
with a (Table 1, entries 1–6), and the most electron-deficient lac-
tam 3 required the least amount of catalyst. Lactam 4 coupled with
a in a lower yield (61%) when catalyst 1 was employed (entry 2);
however, catalyst 2 furnished 4a in 89% yield (entry 3).
The influence of the substituent on the amide nitrogen was evi-
dent when less reactive cross-partners, b and c, were used (Table 1,
Both electron-rich and electron-poor styrenes coupled effi-
ciently with 3 (entries 21 and 22). Notably, the E-selectivity was
higher, which may be a result of increased branching at the
* Corresponding author. Tel.: +1 860 486 3460; fax: +1 860 486 2981.
E-mail address: amy.howell@uconn.edu (A.R. Howell).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.060

Y. Liang et al. / Tetrahedron Letters 50 (2009) 1020–1022
1021
Table 1
CM reactions of lactams 3–7
underwent CM to give trisubstituted alkenes (see Scheme 1)
prompted us at that time to attempt the preparation of tetrasubsti-
tuted alkenes. This was unsuccessful. However, in contrast to our
NR
NR
O
Catalyst 1 or 2
a
-methylene-b-lactones that had relatively large substitutents at
C-4, most of our -methylene-b-lactams were unsubstituted at
that position. Consequently, we decided to examine CM between
the most reactive -methylene-b-lactam 3 and terminal disubsti-
R'
R'
a
CH2Cl2, reflux
O
a: R' = (CH2)2CH3
b: R' = (CH2)2OAc
c: R' = CH2Cl
3: R = Boc
a
4: R = H
tuted alkenes. The results are shown in Table 2.
5: R = Bn
6: R = Ph
d: R' = p-MeOPh
e: R' = p-FPh
CM reactions between 3 and various disubstituted alkenes (Ta-
ble 2, entries 1–8) proceeded in moderate to excellent yields and
with little to no stereoselectivity. Comparing the conditions and re-
sults of entries 1–3 with the preparations of trisubstituted alkenes
3a–c (Table 1, entries 1, 8, and 15), the CM reactions to give tetra-
substituted alkenes generally required more catalyst. Compatible
functional groups included ester,9 phenyl, trimethylsilyl, and
unprotected alcohol groups (Table 2, entries 4–7). 3-Methyl vinyl
acetate, however, did not undergo CM reaction with 3 (entry 8),
presumably due to the electronic nature of the vinyl acetate. In
most cases, 10 mol % loading of catalyst 2 was required to reach
a reasonable conversion.
7: R = p-MeOPh
f: R' = CH2OH
Entry
Reactants
Product
Catalyst (loading)
Yield (%)
E:Za
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3, a
4, a
4, a
5, a
6, a
7, a
3, b
3, b
4, b
5, b
6, b
7, b
7, b
3, c
3, c
4, c
4, c
5, c
6, c
7, c
3, d
3, e
3, f
3a
4a
4a
5a
6a
7a
3b
3b
4b
5b
6b
7b
7b
3c
3c
4c
4c
5c
6c
7c
3d
3e
3f
1 (2 mol %)
84
61
89
89
82
80
57
90
90
77
76
57
72
NR
78
25
60
58
54
48
87
90
77
2.5:1
2:1
2:1
2:1
3:1
2.5:1
2:1
2:1
2:1
1.5:1
2:1
1.5:1
1.5:1
—
1.2:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
5:1
1 (2 mol % ꢀ 3)
2 (1 mol % ꢀ 3)
1 (2 mol % ꢀ 2)
1 (2 mol % ꢀ 2)
1 (2 mol % ꢀ 2)
1 (2 mol % ꢀ 5)
2 (1 mol % ꢀ 3)
2 (1 mol % ꢀ 3)
2 (1 mol % ꢀ 3)
2 (1 mol % ꢀ 3)
2 (1 mol % ꢀ 3)
2 (2 mol % ꢀ 5)
1 (2 mol % ꢀ 3)
2 (5 mol %; 1 mol %)
2 (5 mol %; 1 mol %)
2 (3 mol % ꢀ 3)
2 (5 mol %; 1 mol %)
2 (5 mol %; 1 mol %)
2 (5 mol %; 1 mol %)
2 (1 mol % ꢀ 3)
2 (1 mol % ꢀ 3)
2 (2 mol % ꢀ 5)
The substituents of the cross-partners could be extended (from
Me to Et) without diminishing the reactivity of CM (Table 2, entry
9). However, any a
-branching on the allylic position10 appeared to
shut down the CM reaction completely (Table 2, entries 10 and 11).
On the other hand, CM reaction of 3 with 2-methyl-1-penten-3-ol,
which bears an allylic alcohol, proceeded in moderate yield with an
E:Z ratio of 1:2.5 (entry 12). The yield was further improved to 69%
by using increased catalyst loading and extended refluxing (entry
13).
To further clarify the role that steric factors play in CM reac-
tions, the reactivity of 10, which contains a methyl group on C-4
of the lactam, with 2-methyl-1-pentene was examined (Table 3,
entry 1). No cross-product was observed. On the other hand, the
CM reactions to form tetrasubstituted alkenes could take place
3:1
2:1
a
Determined by 1H NMR.
when an electron-rich a-methylene-b-lactam 5 was employed (en-
try 2), which may suggest that the electronic effects are not as
important as steric effects in these reactions.
a
-carbon of the alkene. Additionally, CM of 3 with unprotected al-
lyl alcohol, which did not undergo CM with
a-methylene-b-lac-
tones,5 gave a good yield of 3f, although increased catalyst
loading was required (entry 23).
Additional support for a prominent role for steric effects is seen
in the contrast in CM reactivity of enoates 12 and 13.
a-Methyl-
The stereoselectivity of CM reactions can be quite varied, but
substituted enoate 12 was reported to undergo CM with a simple,
terminal alkene in the presence of catalyst 1 in excellent yield with
generally, E-isomers predominate.4,6 However, our initial investi-
gations5 involving CM of exocyclic enones evaluated an
a-methy-
lene-b-lactone with a bulky substituent at C-4, which led to CM
adducts with high Z-selectivity (Scheme 1). In comparison, CM
Table 2
reactions with a-methylene-b-lactams 3–7, which have no substi-
CM reactions of a-methylene-b-lactam 3 with 1,1-disubstituted alkenes
tuent at C-4, gave rise to cross-products that were slightly E-selec-
tive.7 To assess the steric influence that C-4 substitution imposes
NBoc
O
NBoc
O
R
Catalyst 2
on the E:Z ratio,
2). When 8 was reacted with b under the conditions developed
for 4 (Table 1, entry 9), -alkylidene-b-lactam 8b was isolated in
a-methylene-b-lactam 8 was examined (Scheme
R'
CH2Cl2, reflux
R'
R
a
9
3
81% with an E/Z ratio of 1:3. Thus, a group as small as methyl sig-
nificantly impacted the E/Z selectivity.
Entry
R
R0
Catalyst loading
Yield (%)
E:Za
Unlike the successful construction of tetrasubstituted cycloalk-
enes via ring-closing metathesis (RCM),8 CM reactions to give tet-
rasubstituted alkenes have not yet been reported to our
1
2
3
4
5
6
7
8
9
10
11
12
13
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
CH2CH2CH3
CH2CH2OAc
CH2Cl
CH2COOEt
CH2Ph
CH2SiMe3
CH2OH
OAc
2 mol % ꢀ 3
2 mol % ꢀ 3
2 mol % ꢀ 5
2 mol % ꢀ 5
2 mol % ꢀ 5
2 mol % ꢀ 5
2 mol % ꢀ 5
2 mol % ꢀ 3
2 mol % ꢀ 5
2 mol % ꢀ 3
2 mol % ꢀ 3
2 mol % ꢀ 5b
5 mol % ꢀ 3c
85
64
58
41
81
73
86
NR
65
NR
NR
40
69
1:1
1:1.5
1:1.6
1:1.5
1:1.5
1:1.7
1:1.7
—
—
—
—
1:2.5
1:2.5
knowledge. The facility with which
a-methylene-b-lactones
R
R
4
Et
NH
NH
2 (1 mol% x 3)
CH(CH3)2
Ph
CH(OH)C2H5
CH(OH)C2H5
R'
CH2Cl2, reflux
O
O
AcO
4: R = H
4b: R = H, 90%, E/Z = 2:1
8b: R = CH3, 81%, E/Z = 1:3
a
Determined by 1H NMR.
The reaction was refluxed for 12 h after the last addition of the catalyst.
The reaction was refluxed for 12 h after each addition of the catalyst.
8: R = CH3
b
c
Scheme 2. The impact of C-4 branching on CM reactions.

1022
Y. Liang et al. / Tetrahedron Letters 50 (2009) 1020–1022
Table 3
Acknowledgments
Investigation of steric and electronic effects
We thank Krystle T. Clarke (Houston-Tillotson University) and
R1
R1
4
Laura Allen (Ohio Northern University) for conducting preliminary
experiments. Helpful discussions with Bob Grubbs and Martha
Morton are also acknowledged.
NR
NR
2, 2 mol % x 5
CH2Cl2, reflux
O
O
10, R = Boc, R1 = Me
Supplementary data
5, R = Bn, R1 = H
11, R = Bn, R1 = H
The supplementary data include detailed experimental proce-
dures, characterization data, and 1H and 13C spectra for previously
unreported compounds. Supplementary data associated with this
Letter can be found, in the online version, at doi:10.1016/
j.tetlet.2008.12.060.
Entry
R
R1
Catalyst loading
Yield (%)
E:Za
1
2
Boc
Bn
Me
H
2 mol % ꢀ 3
2 mol % ꢀ 5
NR
74
—
1:1.2
a
Determined by 1H NMR.
high E-selectivity.6b However, we found that, under similar condi-
tions and with 1-pentene as a cross-partner, enone 13 did not react
at all. The result was the same with extended reaction times and
higher catalyst loading with either 1 or 2. Sensitivity to steric ef-
fects is further illustrated by the failure of amide 14 to undergo
CM with disubstituted terminal olefin 3-methylbut-3-enyl acetate
(see alkene for entry 2, Table 2) in the presence of either catalyst 1
or 2, even with high catalyst loading and extended reaction time.
References and notes
1. For recent reviews, see: (a) Sandanayaka, V. P.; Prashad, A. S. Curr. Med. Chem.
2002, 9, 1145; (b) Buynak, J. D. Curr. Med. Chem. 2004, 11, 1951 and references
therein.
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Meester, P.; Chu, S. C. J. Org. Chem. 1985, 50, 4245; (b) Brickner, S. J.; Gaikema, J.
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57, 273.
3. (a) Saalfrank, R. W.; Paul, W.; Liebenow, H. Angew. Chem. 1980, 92, 740; (b)
Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K. Heterocycles 1988, 27,
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Biomol. Chem. 2003, 1, 2670; (e) Basak, A.; Ghosh, S. C. Synlett 2004, 1637;
(f) De Vitis, L.; Troisi, L.; Granito, C.; Pindinelli, E.; Ronzini, L. Eur. J. Org.
Chem. 2007, 2, 356.
4. For recent reviews on cross metathesis, see: (a) Connor, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900; (b) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.;
Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360; (c) Grubbs, R. H. Tetrahedron
2004, 60, 7117; (d) Netscher, T. J. Organomet. Chem. 2006, 691, 5155.
5. Raju, R.; Howell, A. R. Org. Lett. 2006, 8, 2139.
The broad CM reactivity of
a-methylene-b-lactones and -lactams
in contrast to the limited reactivity of 1,1-disubstituted enoates
and enamides suggests that these strained heterocycles could find
utility as masked enoates and enamides.
CO2CH3
12
In conclusion, it has been shown that
CO2CH3
CONH2
14
-methylene-b-lactams
13
a
6. (a) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751; (b) Chatterjee, A. K.;
Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783; (c)
Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E. Org. Lett. 2001, 3, 2209.
7. E/Z isomeric ratio was determined by 1H NMR. Resonances for the exocyclic
alkene proton, for all b-lactam cross products, were consistent with our NOE
undergo efficient CM reactions. Notably, for the first time, the
application of CM to the formation of tetrasubstituted alkenes
has been demonstrated. The observation that electron-poor
lactams exhibit superior reactivity to electron-rich lactams is
consistent with the CM reactivity profile of monosubstituted
based E/Z assignments of a-alkylidene-b-lactones.
8. (a) Yao, Q.; Zhang, Y. J. Am. Chem. Soc. 2004, 126, 74; (b) Michrowska, A.; Bujok,
R.; Harutyunyan, S.; Sashuk, V.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318; (c)
Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912; (d) Nosse, B.; Schall, A.;
Jeong, W. B.; Reiser, O. Adv. Synth. Catal. 2005, 347, 1869; (e) Berlin, J. M.;
Campbell, K.; Ritter, T.; Funk, T. W.; Chlenov, A.; Grubbs, R. H. Org. Lett. 2007, 9,
1339; (f) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.;
Schrodi, Y. Org. Lett. 2007, 9, 1589.
9. Interestingly, during the silica gel chromatographic purification of entry 4
(Table 2), there was significant isomerization of the exocyclic alkenes to the
corresponding a,b-unsaturated esters (see Supplementary data).
10. (a) Courchay, F. C.; Baughman, T. W.; Wagener, K. B. J. Organomet. Chem.
a
,b-unsaturated amides.11 Interestingly, C-4 unsubstituted lactams
3-7 do not undergo CM with substantial E-selectivity. However,
substitution at C-4 (substrate 8) led to Z-selectivity without dimin-
ished reactivity for the
with the CM of -methylene-b-lactones. The impact of allylic
branching on CM reactivity has also been illustrated. Overall,
-methylene-b-lactones and -lactams are excellent substrates for
a-methylene-b-lactam, which is consistent
a
a
CM reactions, and they can be viewed as masked 1,1-disubstituted
enoates and enamides, which have very limited or nonexistent CM
reactivity. Our results also suggest that steric factors play a domi-
nant role in both stereoselectivity and feasibility of CM reactions.
2006, 691, 585; (b) Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. Org. Lett. 2008,
10, 441.
11. Choi, T.-L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2001, 40,
1277.