Nitrogen ylide-mediated cyclopropanation of lactams and lactones

Article abstract of DOI:10.1016/j.tetlet.2010.04.021

Cyclopropanation of α,β-unsaturated δ-lactams and δ-lactones mediated by nitrogen ylides is described. The process tolerates different alkyl halides and gives efficiently bicyclo[4.1.0]heptanes in a totally stereoselective manner. On the other hand, ε-lac

Full text of DOI:10.1016/j.tetlet.2010.04.021

Tetrahedron Letters 51 (2010) 3095–3098
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Tetrahedron Letters
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Nitrogen ylide-mediated cyclopropanation of lactams and lactones
*
Irene Suarez del Villar, Ana Gradillas, Gema Domínguez, Javier Pérez-Castells
Dpto. De Química, Facultad de Farmacia, Universidad San Pablo-CEU, Boadilla del Monte, 28668-Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclopropanation of a,b-unsaturated d-lactams and d-lactones mediated by nitrogen ylides is described.
Received 2 March 2010
Revised 6 April 2010
Accepted 7 April 2010
Available online 11 April 2010
The process tolerates different alkyl halides and gives efficiently bicyclo[4.1.0]heptanes in a totally
stereoselective manner. On the other hand, -lactams under our experimental conditions suffer a novel
process involving a skeletal reorganization to give a bicyclic[3.3.0] system.
Ó 2010 Elsevier Ltd. All rights reserved.
e
Keywords:
Lactams
Lactones
Cyclopropanation
Nitrogen ylides
Rearrangements
1. Introduction
in Table 1. The syntheses of the starting materials were accom-
plished from d-valerolactam 1a by protection and conversion of
Cyclopropanes are a key structural motif in biologically active
natural and non-natural compounds.1 Among the various methods
available for the cyclopropanation of unsaturated compounds, a
great effort has been placed on catalytic decomposition of diazocom-
pounds mediated by metal complexes2 and catalytic Simmons–
Smithreactions.3 Furthermore, the ylide-mediatedcyclopropanation
has received high attention recently.4 Most contributions, however,
deal with sulfonium ylides whereas there are few examples that
use nitrogen-derived ylides.5 Gaunt’s group was the first to report a
truly catalytic cyclopropanation reaction with ammonium ylides
using a tertiary amine as the catalyst.6 Recently, this new organocat-
alyzed cyclopropanation approach was performed enantioselective-
ly using chiral tertiary amines derived from alkaloids.7
Bicyclo[4.1.0]heptanes are interesting structures present in var-
ious biologically active compounds.8 Our group has recently initi-
ated the search for new azabicyclo[4.1.0]heptane compounds
with potential activity against human isoform of nitric oxide syn-
thase (iNOS).9
We were interested in the cyclopropanation of unsaturated lac-
tams and lactones, and we envisioned the use of the nitrogen-
ylide-based methodology to obtain the corresponding bicy-
clo[4.1.0]heptanes in an efficient and environmentally friendly way.
lactams 2a–b into their a,b-unsaturated analogues via selenoxide
elimination (Scheme 1). Then, a stoichiometric reaction was car-
ried out using DABCO (1,4-diazabicyclo[2.2.2]octane) or DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene), as tertiary amines, exploring
different solvents, bases and temperatures. The model compound
3a was reacted with phenacyl bromide, adding this reagent slowly
with a pump syringe to avoid side reactions. The reactions gave
cyclopropane 4a in different yields. Only the trans isomer of 4a
was detected in all the reactions.10 Acetonitrile turned to be better
solvent than dichloroethane (DCE) with which we only isolated a
23% yield of 4a (entries 1 and 2). Reaction time was set to 12 h
as no improvement was observed when prolonging to 24 h (entries
2 and 3). The base of choice was Cs2CO3. The use of harder bases
(Na2CO3, NaOH, entries 5 and 6), led to the formation of variable
amounts of another product, 5a, as a result of a Morita–Baylis–Hill-
man-type reaction. Thus, the enolate resulting from the reaction of
3a with DABCO reacts with another molecule of 3a, with further
recovery of the double bond. Michael type dimers are known to
be formed in Morita–Baylis–Hillman reactions as side products be-
cause they themselves act as electrophiles.11
In general, the addition of NaI was favourable, increasing the
conversion of the reaction (compare entries 1 with 2; 3 with 4; 7
with 8 and 9 with 10). On the other hand, DABCO was the best cat-
alyst as the use of DBU led to significant lower yields (entries 7 and
8). Once the best stoichiometric conditions were found (entry 4),
we switched to catalytic reactions using 0.2 equiv of DABCO (entry
9). Although we obtained the desired product, the yields were low.
Therefore we continued the study using stoichiometric amounts of
DABCO.12
2. Results and discussion
We have prepared two differently protected d-lactams, 3a–b,
and submitted them to a set of reaction conditions summarized
* Corresponding author. Tel.: +34 913724700; fax: +34 913510496.
E-mail address: jpercas@ceu.es (J. Pérez-Castells).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.021

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Irene Suarez del Villar et al. / Tetrahedron Letters 51 (2010) 3095–3098
Table 1
Reaction conditions for the cyclopropanation of 3a with phenacyl bromide
No.
Cat.a
Base 1.2 equiv
Solv.
Time (h)/T (°C)
Additive 40 mol %
Yield (%)
3a
4a
5a
1
2
3
4
5
6
7
8
9
DABCO
DABCO
DABCO
DABCO
DABCO
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
NaOH
Cs2CO3
Cs2CO3
Cs2CO3
DCE
DCE
12/80
24/80
24/80
12/80
12/80
12/80
12/80
12/80
12/80
85
45
30
10
30
—
90
77
46
10
23
50
68
10
—
3
15
23
NaI
NaI
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
50
90
DBU
DBU
NaI
NaI
DABCO (0.2 equiv)
a
1 equiv except entry 9.
Once the reaction conditions had been selected (Table 1, entry
4), we studied the scope of this synthesis by selecting various
bromoketones (Scheme 2, Table 2).
(Boc)2O
DMAP, Et3N
or
1) LHMDS , PhSeCl
2) m-CPBA
First we carried out the reaction with compound 3b and phena-
cyl chloride observing a better behaviour of this substrate, as we
reached a yield of 75% for the final product (Table 2, entry 1). Sub-
strate 3a gave poor results with the different chlorides used. We
were able to isolate a low yield of 4c when using tert-butyl bromo-
acetate as the electrophile (30%, entry 2). On the other hand this
halide gave a good yield of cyclopropane 4d when reacting with
3b. This result was achieved using an excess of DABCO and NaI
(entries 3 and 4). We did not observe any reaction of 3a with triflu-
orobromoacetone, whereas 3b gave a 57% of the desired cyclopro-
pane 4e along with 25% of 5b (entries 5 and 6).
N
P
O
N
H
1a
O
NaH, p-TsCl
P = Boc; 2a, 80%
P = Ts; 2b, 59%
O
O
Boc
H
6
7
N
Ph
H
Ph
Br
1 H
O
+
N
P
O
conditions,
Table 1
N
Boc
4a
O
N
O
Boc
5a
P = Boc; 3a, 55%
P = Ts; 3b, 61%
At this point we considered extending the methodology to a,b-
unsaturated lactones. Thus, we reacted 5,6-dihydro-2H-pyran-2-
one with phenacyl bromide obtaining an excellent yield in
cyclopropane 4f (80%, entry 7). This lactone gave a good yield of
product 4g in its reaction with tert-butyl bromoacetate (65%, entry
8), but failed to react with the trifluoromethyl containing electro-
phile (entry 9). All the cyclopropanes obtained had trans stereo-
chemistry, never detecting the cis isomers. The assignment of the
relative stereochemistry was realized by NOE experiments that
agreed with the values of the coupling constants.10
Our next aim was to apply this methodology to seven-mem-
bered lactams. Thus, we prepared substrate 3c, following a similar
procedure as for the preparation of 3a–b (Scheme 3). The prepara-
tion of 3c gave an excellent yield of this compound (71%, three
steps from 1b). When we submitted 3c to our reaction conditions
with phenacyl bromide (Table 1, entry 4), we did not detect any
cyclopropane-containing product. However, a new product was
formed in 55% yield. The structure of this compound was estab-
lished by NMR methods and was further confirmed by an X-ray dif-
fraction analysis (see Fig. 1 for an ORTEP illustration).13 Increasing
the amount of base to 2 equiv of Cs2CO3 allowed us to raise the
Scheme 1. Synthesis of starting lactams and study of cyclopropanation conditions.
O
O
H
X
H
R
+
Br
R
O
H
O
DABCO
O
CH3CN, 0.25M
X
X
O
X
Cs2CO3 (1.2 eq.)
3
5
4
O
O
N
N
+
+
N
N
R
R
-
X
O
Scheme 2. Synthesis of cyclopropanes 4 and reaction course.
Table 2
Scope of the cyclopropanation reaction
No.
X
R
DABCO equiv
Add. 40 mol %
Time (h)/T (°C)
Yield (%)
4
3
5
1
2
3
4
5
6
7
8
9
NTs
NBoc
NTs
NTs
NBoc
NTs
O
Ph
1.3
1
1.3
1.8
1
1.8
1.5
1.5
1.5
NaI
NaI
—
NaI
NaI
NaI
NaI
NaI
NaI
12/80
12/80
24/80
48/80
72/80
24/80
12/80
12/80
72/80
16
25
17
17
65
24
—
4b: 75
4c: 30
4d: 35
4d: 65
—
4e: 57
4f: 80
4g: 65
—
—
OtBu
OtBu
OtBu
CF3
35
32
12
34
25
—
CF3
Ph
O
O
OtBu
CF3
—
95
—
—

Irene Suarez del Villar et al. / Tetrahedron Letters 51 (2010) 3095–3098
3097
O
H
Ph
O
H
DABCO (1 eq.)
Cs2CO3 (1.2 eq.)
NaH,
1) LHMDS,
PhSeCl
Ph
p-TsCl
O
H
O
N
Ts
CH3CN, 80ºC, 12h.
O
2) m-CPBA
N
Ts
N
H
N
Ts
O
O
N
Ts
O
(1.5 eq.)
Ph
6 (55%)
not detected
2c (85%)
1b
3c (83%)
Br
base
+
+
+
R3N
R3N
Ph
O
R3N
+
Ph
NR3
Ph
Ph
H
+
R3N
O
Ph
O
O
N
Ts
O
N
Ts
H
N
Ts
C
O
O
O
O
N
Ts
N
H2O
Ts
A
B
D
E
Scheme 3. Synthesis and reaction course for product 6.
Acknowledgements
Funding of this project by Spanish MEC (No. CTQ2009-007738/
BQU) and FUSP-CEU (PC16/09) is acknowledged. I.S.-V. thanks the
Fundación San Pablo-CEU for pre-doctoral fellowship.
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic data and spectra for new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.04.021.
References and notes
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8627; (c) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789–2834;
(d) Burgess, K.; Ho, K.-K.; Moye-Sherman, D. Synlett 1994, 575–583; (e) Li, A.-
H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341–2372.
2. Maas, G. Chem. Soc. Rev. 2004, 33, 183–190; Recent examples: (a) Schneider, T.
F.; Kaschel, J.; Dittrich, B.; Werz, D. B. Org. Lett. 2009, 11, 2317–2320; (b)
Ruppel, J. V.; Gauthier, T. J.; Snyder, N. L.; Perman, J. A.; Zhang, X. P. Org. Lett.
2009, 11, 2273–2276; (c) Gregg, T. M.; Farrugia, M. K.; Frost, J. R. Org. Lett. 2009,
11, 4434–4436.
3. Taylor, R. E.; Engelhardt, F. C.; Schmitt, M. J. Tetrahedron 2003, 59, 5623–5634;
For recent methylene transfer reactions see also: (a) Zimmer, L. E.; Charette, A.
B. J. Am. Chem. Soc. 2009, 131, 15624–15626; (b) Hardee, D. J.; Lambert, T. H. J.
Am. Chem. Soc. 2009, 131, 7536–7537.
4. (a) Yamada, S.; Yamamoto, J.; Ohta, E. Tetrahedron Lett. 2007, 48, 855–857; (b)
McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org. Chem. 2006, 71, 7494–7497; (c)
Kojima, S.; Hiroike, K.; Ohkata, K. Tetrahedron Lett. 2004, 45, 3565–3568; (d) Ye,
S.; Huang, Z.-Z.; Xa, C.-A.; Tang, Y.; Dai, L.-X. J. Am. Chem. Soc. 2002, 124, 2432–
2433; (e) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni,
M. Angew. Chem., Int. Ed. 2001, 41, 1433–1436.
5. Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596–5605.
6. Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2003, 42, 828–
831.
7. (a) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2004, 43, 4641–4644; (b) Bremeyer, N.; Smith, S. C.; Ley, S. V.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43, 2681–2684; (c) Johansson, C. C. C.;
Bremeyer, N.; Owen, D. M.; Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2006, 45, 6024–6028.
8. Xu, R.; Li, S.; Paruchova, J.; McBriar, M. D.; Guzik, H.; Palani, A.; Clader, J. W.;
Cox, K.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O’Neil, K.; Spar, B. D.; Weig,
B.; Weston, D. J. Bioorg. Med. Chem. 2006, 14, 3285–3599.
9. Suarez del Villar, I.; Gradillas, A.; Gómez-Ovalles, A.; Martínez-Murillo, R.;
Martínez, A.; Pérez-Castells, J. Chem. Lett. 2008, 37, 1222–1223.
10. The assignment of the relative stereochemistry of the cyclopropane was done
by NOE experiments (see Supplementary data) and confirmed with the values
of the coupling constants which were the typical for a trans cyclopropane
(J1,7 = 4.1 Hz/4.9 Hz).
Figure 1. ORTEP drawing for compound 6 with ellipsoids at 50% probability.
yield in 6 up to 70%. We show in Scheme 2 a reaction course that
could explain the formation of 6.
The reaction must begin with the formation of the lactam enolate
A that attacks the carbonyl group of the ammonium salt formed by
reaction of DABCO with the bromoketone. To check this point we
performed a reaction in the absence of DABCO observing no conver-
sion into product 6. Once zwitterionic intermediate B is formed, a
process possibly of type E1cB would drive to intermediate C. The sta-
bilization exerted by the phenyl group must be critical to favour the
elimination step as the reaction with other bromoketones or bromo-
esters did not take place. Indeed, we carried out reactions with
trifluoromethyl bromomethylketone and with tert-butyl bromoace-
tate observing no reaction, and recovering the starting material.
Lactam C must be opened under these basic conditions giving D
whose amino group attacks the a,b-unsaturated acid moiety provid-
ing E. This intermediate suffers a second cyclization by elimination
of DABCO to give finally product 6. This compound is obtained with
cis stereochemistry at the ring fusion.
In conclusion, we have developed the synthesis of new cyclo-
propane containing lactams and lactones through an efficient
nitrogen ylide-mediated procedure. The reaction tolerates different
alkyl halides. The behaviour of the seven-membered lactam 3c was
especially interesting due to a rearrangement leading to a bicyclic
compound consisting of two five-membered rings. Further exten-
sion of this process to other substrates is underway in our
laboratories.

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Irene Suarez del Villar et al. / Tetrahedron Letters 51 (2010) 3095–3098
11. See: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–
891; (b) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511–4574.
12. General procedure for the synthesis of compounds 4. DABCO (1–1.8 equiv) was
Cs2CO3 (0.85 g, 2.43 mmol), DABCO (0.22 g, 2.02 mmol), NaI (0.12 g,
0.81 mmol) and 3a (0.4 g, 2.02 mol). Reaction time: 12 h at 80 °C. Yield:
0.23 g (60%; hexane: EtOAc, 7:3). 10% of 3a was recovered. 1H NMR (CDCl3,
300 MHz) d ppm: 1.51 (s, 9H, 3CH3); 2.13–2.15 (m, 2H, CH2); 2.33–2.36 (m,
1H, H6); 2.58 (dd, 1H, J1 = 8.5 Hz, J2 = 4.2 Hz, H1); 3.20–3.30 (m, 1H, CH2);
3.40 (dd, 1H, H7, J1 = 4.3 Hz, J2 = 4.2 Hz); 4.08 (dt, 1H, CH2, J1 = 14.0 Hz,
J2 = 3.6 Hz); 7.47 (t, 2H, ArH, J = 7.3 Hz); 7.58 (t, 1H, ArH, J = 7.3 Hz); 7.93 (t,
2H, ArH, J = 7.3 Hz). 13C NMR (CDCl3, 75 MHz) d ppm: 20.4, 25.1, 25.9, 28.0,
31.0, 41.0, 83.5, 128.2, 128.7, 133.5, 136.9, 152.2, 168.1, 195.4. IR (KBr)
2980, 2910, 1760, 1720, 1670, 1590, 1449 cmÀ1. Anal. Calcd for C18H21NO4
(315.36): C, 68.55; H, 6.71; N, 4.44. Found: C, 68.63; H. 6.50; N. 4.48.
13. Data can be obtained free of charge from The Cambridge Crystallographic Data
Centre, CCDC.
added to
a stirred solution of the alkyl halide (1 equiv) in dry MeCN
(0.25 M) and stirred at rt for 60 min. The base (1.5 equiv) and NaI (0.4 equiv)
were added, followed by lactam 3a–c (1 equiv). The reaction mixture was
stirred at 80 °C. Once completed, as shown by TLC analysis, the reaction was
quenched with saturated aqueous ammonium chloride solution (15 mL) and
the reaction mixture was extracted with Et2O (2 Â 20 mL). The combined
organic phases were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography. Synthesis of
*
*
*
(1R ,6R ,7R )-7-benzoyl-2-oxo-3-aza-bicyclo[4.1.0]heptane-3-carboxylic
acid
tert-butyl ester, 4a. From -bromo benzophenone (0.40 g, 2.02 mmol),
a