Advancing the reactivity of dimethylcyclopropane-1,1-dicarboxylates via cross metathesis

Article abstract of DOI:10.1055/s-0033-1340460

Cross metathesis of the readily available dimethyl 2-vinylcycloropane-1,1- dicarboxylate with a variety of olefins gave divergent access to new donor-acceptor cyclopropanes bearing a π-donor alkenyl substituent. The synthetic utility of these cyclopropanes was shown by their participation in cycloaddition reactions with nitrones to yield the anticipated tetrahydro-1,2-oxazines. Hydrogenation yielded the alkyl-substituted adducts which would be more difficult to access via other means. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340460

428▌
LETTER
lAettder vancing the Reactivity of Dimethylcyclopropane-1,1-dicarboxylates via
Cross Metathesis
Reactivity of Dimethylcyclopropane-1,1-dicarboxylates
Matt R. Vriesen, Huck K. Grover, Michael A. Kerr*
Department of Chemistry, The University of Western Ontario, London, ON, N6A 5B7, Canada
Fax +1(519)6613022; E-mail: makerr@uwo.ca
Received: 21.10.2013; Accepted after revision: 19.11.2013
One strategy to circumvent the lack of reactivity of cyclo-
Abstract: Cross metathesis of the readily available dimethyl 2-vin-
propanes bearing a simple alkyl substituent3 is to employ
ylcycloropane-1,1-dicarboxylate with a variety of olefins gave di-
the corresponding alkenyl cyclopropane 1 (Scheme 2) and
to saturate the double bond in 2 post-cycloaddition to
vergent access to new donor–acceptor cyclopropanes bearing a π-
donor alkenyl substituent. The synthetic utility of these cyclopro-
panes was shown by their participation in cycloaddition reactions yield 3. This would obviate the use of the less reactive cy-
with nitrones to yield the anticipated tetrahydro-1,2-oxazines. Hy-
drogenation yielded the alkyl-substituted adducts which would be
more difficult to access via other means.
clopropane 4. While this is certainly a good strategy, the
requisite cyclopropanes 1 bearing a variety of alkenyl
groups may be difficult to prepare using typical cyclo-
propanation methods (Corey–Chaykovsky4 or carbenoid
Key words: heterocycles, cycloaddition, cyclopropanes, metathe-
sis, ruthenium
insertion5). The simple parent 2-vinyl cyclopropane-1,1-
dicarboxylate (1; R = H) is, on the other hand very readily
available in large quantities and in racemic6 or
enantioenriched7 form. Herein we present a divergent
strategy involving cross metathesis for the synthesis of a
wide variety of dimethyl 2-alkenylcyclopropane-1,1-di-
carboxylates from simple starting materials and their use
in circumventing difficulties in cycloaddition chemistry.
Advances in the synthetic utility of donor–acceptor cyclo-
propanes are appearing at an ever increasing rate.1 The
importance of these seemingly simple molecules is evi-
dent by their use in complex natural product synthesis.2
Useful reactions of these molecules I, include both nu-
cleophilic ring opening as well as cycloaddition (or annu-
lation) processes to yield III or V, respectively (Scheme
1). Both types of transformations require an acceptor moi-
ety and a donor moiety vicinally disposed. The ‘donor’
group can be any functional group capable of stabilizing a
developing positive charge in the transitions states (II or
IV) in the ring opening event. Our research group has a
longstanding interest in cyclopropane-1,1-dicarboxylates
1 (vide infra) as tools for synthesis. The substrates which
behave the best by far are those bearing an aryl or vinyl
group vicinal to the geminal diester. While simple alkyl
moieties at this position are tolerated, the reaction times
are longer and the yields are typically lower.
The literature is surprisingly sparse in examples8,9 of the
cross metathesis of vinyl cyclopropanes and to our knowl-
edge, there are no examples using donor–acceptor cyclo-
propanes. Our initial investigations (shown in Table 1)
into the cross metathesis of dimethyl 2-vinylcyclopro-
pane-1,1-dicarboxylate (5) and 1-hexene focused on de-
termining the appropriate catalyst and conditions for this
reaction. Grubbs 1st, 2nd and Grubbs–Hoveyda 2nd genera-
tion catalysts10 were all screened and it was determined
that Grubbs 2nd generation catalyst was required to ensure
complete conversion of starting materials for the desired
metathesis product 6a (Table 1, entries 1–5). Although
both Grubbs 1st and Grubb–Hoveyda 2nd generation cata-
lysts did promote the formation of product, the transfor-
mation never reached completion even with extended
reaction times and increased catalytic loading. The use of
2nd generation Grubbs catalyst allowed for lower catalyst
loadings while giving comparable yields of isolated prod-
uct at 70% and 67% for both 5 mol% and 1 mol%, respec-
tively (entries 1 and 2). In the hope of increasing the
overall yield of the metathesis, the stoichiometry of 1-
hexene was varied (entries 6 and 7). It was quickly ob-
served that lowering the excess of 1-hexene from 1.4
equivalents to 1.2 equivalents greatly decreased the yield
of the desired metathesis product while promoting a large
increase in both cyclopropane and hexene dimerization
by-products. In contrast, increasing the excess of 1-hex-
ene to 2.0 equivalents showed no additional increase in
product yield. Interestingly, when the temperature was de-
creased to room temperature and then to 0 °C (entries 8
and 9) the E/Z product ratio also decreased, along with an
homo-Michael addditon
‡
δ+
EWG
EDG
δ–
Nu
EDG
δ–
Nu
Nu
EWG
II
III
EWG
EDG
δ–
A
δ+
B
A
B
‡
δ–
δ+
I
A
B
EWG
EDG
δ–
δ+
EDG
EWG
IV
cycloaddition or annulation
V
Scheme 1 Donor-acceptor cyclopropanes in addition and cycloaddi-
tion reactions
SYNLETT 2014, 25, 0428–0432
Advanced online publication: 10.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340460; Art ID: ST-2013-R0986-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reactivity of Dimethylcyclopropane-1,1-dicarboxylates
429
cycloaddition
(high-yielding)
olefin reduction
(high-yielding)
R
R
R
R
A
B
A
B
[H]
δ–
δ+
δ–
δ+
A
B
A
B
Lewis acid
catalyst
Lewis acid
catalyst
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
MeO2C
MeO2C
1
2
3
4
direct cycloaddition
(usually lower-yielding)
Scheme 2 Two cycloaddition strategies to adduct 3
overall decrease in yield and increase in reaction time. Fi- available alkyl-substituted olefins (Scheme 3). Gratify-
nally, diethyl ether was employed11 in order to help solu- ingly, 1-hexene, 1-octene, and 1-dodecene underwent the
bilize any unwanted dimer products formed, so that they cross metathesis smoothly giving vinyl cyclopropanes 6a,
remained active product-forming entities (entry 10). Al- 6b, and 6c in 67%, 74%, and 69% yields, respectively
though dimer formation was minimized, the reaction was with little or no observed dimerization products isolated.
sluggish and led to incomplete product conversion even It is noteworthy to mention that with a much longer alkyl
under extended reaction times.
chain (product 6c), the E/Z ratio was reduced to 3:1. More
functionalized olefins also underwent the metathesis effi-
ciently, allowing access to 6d and 6e in good yields. In the
case of 6e, a higher catalyst loading was required to drive
the reaction to completion. Disubstituted alkyl olefins, in-
cluding 2,4,4-trimethylpent-1-ene, were also subjected to
With our best cross-metathesis conditions in hand (Table
1, entry 2), we examined the scope of olefins that would
undergo metathesis with dimethyl 2-vinylcyclopropane-
1,1-dicarboxylate (5). We first studied the use of readily
Table 1 Optimization of Cross Metathesis
MeO2C CO2Me
MeO2C CO2Me
catalyst
conditions
5
6a
N
N
N
N
Mes
Mes
Mes
Mes
(Cy)3P
Cl
Cl
Cl
Ph
Ru
Ru
Ru
O
Cl
Cl
Cl
Ph
P(Cy)3
P(Cy)3
G1
Grubbs 1st
G2
Grubbs 2nd
GH
Grubbs–Hoveyda 2nd
generation catalyst
generation catalyst
generation catalyst
Entry
1-Hexene (equiv)
Catalyst (mol%)
Solvent/temp (°C)
Time
Yield (%) (E/Z)a
1
2
1.4
1.4
1.4
1.4
1.4
1.2
2.0
1.4
1.4
1.4
G2 (5%)
G2 (1%)
G1 (1%)
G1 (10%)
GH (1%)
G2 (1%)
G2 (1%)
G2 (1%)
G2 (1%)
G2 (1%)c
CH2Cl2/reflux
CH2Cl2/reflux
CH2Cl2/reflux
CH2Cl2/reflux
CH2Cl2/reflux
CH2Cl2/reflux
CH2Cl2/reflux
CH2Cl2/r.t.
2 h
3 h
70% (6:1)a
67% (6:1)a
ICb
3
24 h
24 h
24 h
2 h
4
ICb
5
ICb
6
53% (6:1)a
67% (6:1)a
50% (2:1)a
ICb
7
2 h
8
24 h
72 h
40 h
9
CH2Cl2/0 °C
Et2O/reflux
10
ICb
a E/Z ratio determined by 1H NMR.
b IC = incomplete reaction.
c CuI (3 mol%) was also added.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 428–432

430
M. R. Vriesen et al.
LETTER
MeO2C
CO2Me
MeO2C
CO2Me
R
G2 (1 mol%)
R
5
6a–n
CH2Cl2, reflux
alkyl-substituted
MeO2C CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
6a: 67%
(6:1 E/Z)a
6b: 74%
(6:1 E/Z)a
6c: 69%
(3:1 E/Z)a
MeO2C
CO2Me
MeO2C
CO2Me
Br
OTBS
6d: 78%
(4:1 E/Z)a
6e: 73%b
(3:1 E/Z)a
aromatic-substituted
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
6f: 75%b
(E only)a
6g: 29%
(E only)a
6h: 60%
(E only)a
OMe
NO2
electron-deficient olefins
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
OMe
CHO
6i: 69%
(E only)a,c
6j: 82%
(E only)a
6k: 92%
(8:1 E/Z)a
O
O
less reactive substrates
MeO2C CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
TMS
OBoc
6l: 7%
6m: 5%d
6n: 6%e
NTs
Scheme 3 Metathesis scope. a E/Z ratio was determined by 1H NMR. b Increased catalyst loading was required to promote product conversion.
c (E)-But-2-enal was used as the metathesis partner. d Isolated as an inseparable mixture of product and indole dimer. e Isolated as an inseparable
mixture of product and cyclopropane dimer.
the reaction conditions, however only cyclopropane dimer Many modifications were made to increase the yield of 6g
was isolated.
however the p-methoxystyrene proved to be too reactive
and in all cases the dimer was the major isolated product.
Finally, electron-withdrawing p-nitrostyrene underwent
the metathesis with success giving 6h in 60% yield, a re-
sult that could be attributed to the lowered reactivity of the
olefin towards dimerization under these conditions.
We next examined the effects of styrenes as participants
in the cross-metathesis reaction. The reaction of dimethyl
2-vinylcyclopropane-1,1-dicarboxylate (5) and styrene
proved to be difficult due to the increased reactivity of the
starting material towards dimerization as well as polymer-
ization.12 After several attempts at modifying the reaction A variety of electron-deficient α,β-unsaturated olefins
conditions, it was determined that the required metathesis were explored as cross-metathesis partners. The initial
product 6f could be isolated in good yield (75%) when 3 metathesis between 5 and acrolein led to the desired prod-
equivalents of styrene and 2.5 mol% of catalyst were uct 6i, however in a low yield of 33% with significant de-
used. Additionally, the reaction had to be monitored scru- composition of acrolein. To avoid the decomposition of
pulously by TLC until the cyclopropane starting material acrolein, (E)-but-2-enal was used as a substitute and 6i
was consumed. If the reaction was left longer, styrene di- was isolated in 69% yield. Interestingly, methyl vinyl ke-
mer would form rapidly, making purification extremely tone underwent the reaction giving 6j as the sole product
difficult. When p-methoxystyrene was subjected to the re- in 82% yield with no sign of starting material decomposi-
action conditions, the styrene dimer proved to be the ma- tion. Methyl acrylate also showed great success towards
jor product allowing for isolation of 6g in only 29% yield. the metathesis allowing access to 6k in 92% yield.
Synlett 2014, 25, 428–432
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reactivity of Dimethylcyclopropane-1,1-dicarboxylates
431
Although a range of olefins were able to undergo the me- to convert 7a and 7b into their corresponding oxazine
tathesis successfully in modest to excellent yields, there products 9c and 9d in isolated yields of 44% and 25%, re-
were a few substrates that gave poor results. Allyl trimeth- spectively.15
ylsilane proved to be very unreactive towards the metath-
esis allowing for only 7% yield of product 6l under the
reaction conditions, even when increased reaction times
Finally, the tetrahydro-1,2-oxazines were reduced in or-
der to access the alkyl-substituted derivative. Due to the
sensitivity of the tetrahydro-1,2-oxazines N–O bond, a
and catalyst loadings were employed. 1-Tosyl-3-vinylin-
mild tosylhydrazine/sodium acetate reduction was uti-
dole and allyl tert-butyl carbonate both showed limited
lized (Scheme 5). Reduction of 9a and 9b was successful
success undergoing the metathesis in 5% and 6% yields,
leading to isolations of tetrahydro-1,2-oxazines 9c and 9d
in 91% and 98% yield, respectively.
respectively (6m and 6n); however the products were in-
separable from the corresponding dimers.
With adducts such as 6 in hand we set forth to compare the
H
N
MeO2C CO2Me
Tol
MeO2C CO2Me
Tol
reactivity of these cyclopropanes against their saturated
counterparts. In order to secure the corresponding alkyl-
substituted cyclopropanes 7a and 7b (Scheme 4), vinyl
cyclopropanes 6a and 6f were reduced using mild hydra-
zine transfer hydrogenation conditions.13 To test the reac-
tivity of each cyclopropane, a fundamental and well-
studied nitrone cycloaddition reaction was performed.14
Each cyclopropane was subjected to nitrone 8 and catalyt-
ic Yb(OTf)3 in CH2Cl2 for an extended reaction period of
18 hours. Both alkenyl-substituted cyclopropanes 6a and
6f gave excellent conversions to the corresponding tetra-
hydro-1,2-oxazines (9a and 9b) in 96% and 92% yields,
respectively. In contrast, saturated cyclopropane 7a pro-
duced tetrahydro-1,2-oxazine 9c in a 34% (based on re-
covered starting material) yield as an inseparable mixture
of product and starting cyclopropane. Saturated cyclopro-
pane 7b did not react under the standard reaction condi-
tions and only starting material was recovered. If the
reaction conditions were made more severe [20 mol%
Yb(OTf)3 in refluxing 1,2-dichloroethane], it was possible
Ts
NH2
N
N
NaOAc
H2O–THF
Ph
O
R
Ph
O
R
9a,b
9c,d
MeO2C CO2Me
Tol
MeO2C CO2Me
Tol
N
N
Ph
O
Ph
O
9c: 91%
9d: 98%
Scheme 5 Vinyl tetrahydro-1,2-oxazine reduction
In conclusion, we have produced a variety of alkenyl-sub-
stituted cyclopropanes via a cross-metathesis procedure
that utilizes moderately low loadings of Grubbs 2nd gener-
ation catalyst and is applicable to a wide series of ole-
fins.16 Additionally, we have shown that alkenyl-
substituted cyclopropanes can serve as surrogates to ac-
cess products which would normally be formed from al-
kyl-substituted cyclopropanes, allowing for a significant
increase in yield for a given cycloaddition reaction. Mild
olefin reduction conditions allow for quick access to al-
kyl-substituted cycloadducts with high overall yields.
Tol
O
MeO2C CO2Me
Tol
N
MeO2C
CO2Me
R
8
Ph
N
Yb(OTf)3, CH2Cl2
r.t., 18 h
Ph
O
R
Acknowledgment
6 or 7
9a–d
We thank the Natural Sciences and Engineering Research Council
of Canada for generous funding of this research. We are grateful to
Mr. Doug Hairsine of the Western University Mass Spectrometry
facility for performing MS analyses.
6f: R =
7b: R =
Ph
Ph
6a: R =
7a: R =
MeO2C CO2Me
Tol
MeO2C CO2Me
Tol
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
N
N
Ph
O
Ph
O
References and Notes
9a: 96%
(6:1 E/Z)
9b: 92%
(E only)
(1) For reviews on donor–acceptor cyclopropanes, see:
(a) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007,
107, 3117. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005,
61, 321. (c) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003,
103, 1151. (d) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip,
Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
(e) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66.
MeO2C CO2Me
Tol
MeO2C CO2Me
Tol
N
N
Ph
O
Ph
O
(2) (a) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38,
3051. (b) Tang, P.; Qin, Y. Synthesis 2012, 44, 2969.
(3) (a) Zhou, Y.-Y.; Li, J.; Ling, L.; Liao, S.-H.; Sun, X.-L.; Li,
Y.-X.; Wang, L.-J.; Tang, Y. Angew. Chem. Int. Ed. 2013,
9c: 34%a
9d: no reaction
Scheme 4 Comparative nitrone cycloaddition reactions. a Isolated as
an inseparable mixture of product and cyclopropane starting material.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 428–432

432
M. R. Vriesen et al.
LETTER
52, 1452. (b) Emmett, M. R.; Grover, H. K.; Kerr, M. A.
J. Org. Chem. 2012, 77, 6634. (c) Emmett, M. R.; Kerr, M.
A. Org. Lett. 2011, 13, 4180. (d) Grover, H. K.; Lebold, T.
P.; Kerr, M. A. Org. Lett. 2011, 13, 220. (e) Xing, S.; Pan,
W.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem. Int. Ed. 2010,
49, 3215. (f) Pohlhaus, P.; Sanders, S.; Parsons, A.; Li, W.;
Johnson, J. J. Am. Chem. Soc. 2008, 130, 8642. (g) Fang, J.;
Ren, J.; Wang, Z. Tetrahedron Lett. 2008, 49, 6659.
(h) Uddin, M.; Mimoto, A.; Nakano, K.; Ichikawa, Y.;
Kotsuki, H. Tetrahedron Lett. 2008, 49, 5867. (i) England,
D. B.; Kuss, T.; Keddy, R. G.; Kerr, M. A. J. Org. Chem.
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Tetrahedron Lett. 1997, 38, 5949.
136.7, 133.9, 128.6, 127.6, 126.1, 124.5, 52.8, 52.7, 36.0,
31.7, 21.3. IR (thin film): 3027, 2953, 2847, 1731, 1494,
1437, 1283, 1252, 1207, 1128, 964, 770, 744, 694 cm–1.
HRMS: m/z calcd for C15H16O4: 260.1049; found: 260.1049
(only E-olefin observed by 1H NMR).
Dimethyl 2-(3-Oxobut-1-enyl)cyclopropane-1,1-
dicarboxylate (6j): 1H NMR (600 MHz, CDCl3): δ = 6.23–
6.30 (m, 2 H), 3.71 (s, 6 H), 2.56–2.65 (m, 1 H), 2.15 (s, 3
H), 1.78 (dd, J = 7.6, 5.3 Hz, 1 H), 1.72 (dd, J = 8.8, 4.7 Hz,
1 H). 13C NMR (150 MHz, CDCl3): δ = 197.0, 169.0, 167.2,
142.1, 133.3, 52.9, 52.8, 36.5, 29.8, 27.0, 21.5. IR (thin
film): 3007, 2956, 2856, 1731, 1674, 1625, 1438, 1333,
1291, 1253, 1212, 1131, 983 cm–1. HRMS: m/z calcd for
C11H14O5: 226.0841; found: 226.0831 (only E-olefin
observed by 1H NMR).
General Experimental Procedure for the Synthesis of
Tetrahydro-1,2-oxazines 9a–d: Yb(OTf)3·xH2O (5–20 mol
%) was added to a solution of cyclopropane 6a, 6f, and 7a,b
(1 equiv) and nitrone 8 (1.2 equiv) in CH2Cl2 or 1,2-
dichloroethane. Reactions in CH2Cl2 were performed at r.t.,
while reactions in 1,2-dichloroethane were refluxed for 18 h.
The reaction mixture was wet loaded and purified by flash
chromatography (EtOAc–hexanes) to yield the desired
tetrahydro-1,2-oxazine 9a–d.
(4) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 6,
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R.; Jones, R. C. F.; Pritchard, G. J. Chem. Commun. 2004,
21, 2474.
(8) Garcia, P.; Hohn, E.; Pietruszka, J. J. Organomet. Chem.
2003, 680, 281.
(9) Verbicky, C.; Zercher, C. Tetrahedron Lett. 2000, 41, 8723.
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1900. (b) Donohoe, J.; Bower, F.; Chan, L. Org. Biomol.
Chem. 2012, 10, 1322.
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3023.
(15) Product 9d was isolated as an inseparable mixture with
starting cyclopropane.
(16) General Experimental Procedure for the Synthesis of
Substituted Vinyl Cyclopropane 6a–k: Dimethyl 2-
vinylcyclopropane-1,1-dicarboxylate (5; 1 equiv) and olefin
(1.4–5.0 equiv) were dissolved in anhyd CH2Cl2. Grubbs 2nd
generation catalyst (G2; 0.01 equiv) was then added and a
reflux condenser was attached. The reaction vessel was then
purged with argon and the reaction was brought to reflux.
Upon completion by TLC analysis the solvent was removed
and the residue was purified by flash chromatography
(EtOAc–hexanes) to yield the desired cyclopropanes 6a–k.
Analytical Data for Selected Compounds:
Analytical Data for Selected Compounds:
Dimethyl 6-(Hex-1-enyl)-2-phenyl-3-p-tolylmorpholine-
4,4-dicarboxylate (9a): 1H NMR (600 MHz, CDCl3): δ =
7.49–7.56 (m, 2 H), 7.14–7.21 (m, 3 H), 6.91–6.98 (m, 4 H),
5.88–5.97 (m, 1 H), 5.64–5.76 (m, 1 H), 5.62 (s, 1 H), 4.40–
4.47 (m, 1 H), 3.88 (s, 3 H), 3.45 (s, 3 H), 2.44–2.61 (m, 2
H), 2.05–2.11 (m, 5 H), 1.33–1.49 (m, 4 H), 0.95 (t, J = 7.4
Hz, 3 H). 13C NMR (150 MHz, CDCl3): δ = 170.1, 168.4,
146.3, 135.2, 135.0, 130.8, 130.5, 129.0, 127.9, 127.8,
127.7, 116.0, 77.2, 65.9, 59.2, 53.3, 52.5, 32.2, 30.8, 22.3,
22.2, 20.5, 13.9. IR (thin film): 3028, 2954, 2927, 2859,
1742, 1509, 1453, 1434, 1235, 1177, 1149, 1082, 967, 821,
755, 702 cm–1. HRMS: m/z calcd for C27H33NO5: 451.2359;
found: 451.2354. (6:1 trans to cis).
General Experimental Procedure for Olefin Reduction
to Tetrahydro-1,2-oxazines 9c–d: Vinyl tetrahydro-1,2-
oxazines 9a and 9b (1 equiv) were dissolved in THF–H2O
(1:1). Tosylhydrazine (10 equiv) and NaOAc (13 equiv)
were added and the reaction mixture was heated to reflux for
24 h. H2O was added to the reaction and the aqueous layer
was extracted with Et2O (4 ×). The organic phases were
combined and dried with MgSO4, filtered, and the solvent
was removed. The residue was purified by flash
chromatography (EtOAc–hexanes) to yield the desired
tetrahydro-1,2-oxazines (9c and 9d).
Analytical Data for Selected Compounds:
Dimethyl 2-(Hex-1-enyl)cyclopropane-1,1-dicarboxylate
(6a): 1H NMR (400 MHz, CDCl3): δ = 5.71 (dt, J = 15.3, 7.0
Hz, 1 H), 5.35 (ddt, J = 15.2, 8.2, 1.2 Hz, 1 H), 3.72 (s, 6 H),
2.54 (q, J = 8.2 Hz, 1 H), 1.99 (q, J = 7.0 Hz, 2 H), 1.68 (dd,
J = 7.4, 4.7 Hz, 1 H), 1.55 (dd, J = 9.4, 4.7 Hz, 1 H), 1.25–
1.31 (m, 4 H), 0.86 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 170.2, 168.0, 135.6, 124.2, 52.6, 35.6, 32.1,
31.2, 27.5, 27.0, 22.0, 20.8, 13.9. IR (thin film): 3000, 2955,
2929, 2857, 1730, 1437, 1332, 1280, 1260, 1210, 1131 cm–1.
HRMS: m/z calcd for C13H20O4: 240.1362; found: 240.1368
(6:1 trans to cis).
Dimethyl 2-Styrylcyclopropane-1,1-dicarboxylate (6f):
1H NMR (400 MHz, CDCl3): δ = 7.28–7.32 (m, 4 H), 7.20–
7.26 (m, 1 H), 6.65 (d, J = 16.0 Hz, 1 H), 5.81 (dd, J = 16.0,
9.0 Hz, 1 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 2.76 (q, J = 8.2 Hz,
1 H), 1.85 (dd, J = 7.8, 5.1 Hz, 1 H), 1.70 (dd, J = 9.0, 5.1
Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 169.9, 167.9,
Dimethyl 6-Phenethyl-2-phenyl-3-p-tolylmorpholine-
4,4-dicarboxylate (9d): 1H NMR (600 MHz, CDCl3): δ =
7.52–7.56 (m, 2 H), 7.30–7.34 (m, 2 H), 7.26–7.29 (m, 2 H),
7.17–7.24 (m, 4 H), 6.94–7.00 (m, 4 H), 5.67 (s, 1 H), 3.98–
4.07 (m, 1 H), 3.85 (s, 3 H), 3.46 (s, 3 H), 2.96–3.04 (m, 1
H), 2.83–2.91 (m, 1 H), 2.46–2.52 (m, 2 H), 2.13–2.23 (m, 4
H), 1.97–2.06 (m, 1 H). 13C NMR (150 MHz, CDCl3): δ =
170.2, 168.5, 146.4, 141.6, 135.2, 130.7, 130.5, 129.1,
128.4, 128.0, 127.9, 126.0, 115.7, 76.5, 66.0, 59.2, 53.3,
52.5, 36.4, 31.9, 31.0, 20.6 (one carbon missing presumably
due to overlap in the aromatic region). IR (thin film): 3027,
2951, 2924, 2857, 1741, 1509, 1453, 1434, 1236, 1166,
1090, 820, 753, 701 cm–1. HRMS: m/z calcd for C29H31NO5:
473.2202; found: 473.2191.
Synlett 2014, 25, 428–432
© Georg Thieme Verlag Stuttgart · New York

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