Directed Cu(I)-Catalyzed Carbomagnesiation of 1-Arylcycloprop-2-ene-1-carboxamides en Route to Densely Substituted Functionalized Cyclopropanes

Article abstract of DOI:10.1021/acs.joc.8b01063

Copper-catalyzed, directed addition of Grignard reagents across the strained C=C bond of cyclopropene-3-carboxamides was developed. It was demonstrated that the amide functionality serves as an ultimate directing group allowing for highly efficient control of diastereoselectivity of addition including stereoselectivity of electrophilic trapping with prochiral aldehydes. Also, regioselectivity of carbomagnesiation of cyclopropenes with a monosubstituted double bond is investigated. It was shown that in many cases this selectivity is controlled by steric factors and allows for preparation of products with a reversed regiochemistry.

Full text of DOI:10.1021/acs.joc.8b01063

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Article
Directed Cu(I)-Catalyzed Carbomagnesiation of 1-Arylcycloprop-2-ene-1-
carboxamides en route to Densely Substituted Functionalized Cyclopropanes
Andrew Edwards, and Michael Rubin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01063 • Publication Date (Web): 22 Jun 2018
Downloaded from http://pubs.acs.org on June 23, 2018
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The Journal of Organic Chemistry
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Directed Cu(I)-Catalyzed Carbomagnesiation of 1-Arylcycloprop-2-
ene-1-carboxamides en route to Densely Substituted Functionalized
Cyclopropanes
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Andrew Edwards,† and Michael Rubin*,†,‡
†Department of Chemistry, University of Kansas, 1567 Irving Hill Road – Lawrence, KS 66045, USA;
‡Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., Stavropol 355009, Russian Federation.
R1
R2
R1 CONR3R4
CONR3R4
R5
1. CuI (cat)
R5MgX
R2
2. EX
E
Highly diastereoselective
carbomagnesiation
ABSTRACT: Copperꢀcatalyzed directed addition of Grignard reagents across strained C=C bond of cyclopropeneꢀ3ꢀcarboxamides.
It was demonstrated that the amide functionality serves as an ultimate directing group allowing for highly efficient control of diaꢀ
stereoselectivity of addition including stereoselectivity of electrophilic trapping with prochiral aldehydes. Also, regioselectivity of
carbomagnesiation of cyclopropenes with monosubstituted double bond is investigated. It was shown that in many cases this selecꢀ
tivity is controlled by steric factors and allows for preparation of products with “reversed” regiochemistry.
mations include alcohol,7 ester,8 ether,9 and Evans’ chiral oxaꢀ
INTRODUCTION
Carbometalation accompanied by electrophilic trapping is
often regarded to as one of the most important addition reacꢀ
tions of olefins as it allows for efficient installation of two
zolidinone auxiliaries.10 Recently, Marek reported application
of 2ꢀalkylꢀN,Nꢀdimethylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamides (1)
easily available via the wellꢀestablished asymmetric cycloproꢀ
panation methodology,11 in the copperꢀcatalyzed directed
different entities at two adjacent carbon atoms in one operaꢀ
addition of Grignard reagents (Scheme 2).12 Efficient coordiꢀ
tion. This reaction is particularly productive in application to
nation of the organometallic reagent to the carboxamide group
strained olefins, such as cyclopropenes, as it is greatly faciliꢀ
tated by the energy accompanying the strain release.1 Altꢀ
allowed for a highly diastereoselective formation of cycloproꢀ
pyl metal species 2. The subsequent electrophilic trapping
hough nonꢀcatalyzed ringꢀretentive additions of Grignard reaꢀ
with acylsilanes followed by in situ Brook rearrangement
gents across the double bond of cyclopropene have been
known for almost four decades,2 the employment of copper
and iron catalysis took this chemistry to a new level.3 Not only
Scheme 1
did it make this methodology more versatile and efficient,4 it
also advanced the field of enantioselective carbometallation.5
Unless performed on symmetrically substituted cyclopropenes,
the facial selectivity in these reactions was governed by steric
demands, driving the addition of organometallic species to the
least hindered face of the ring. Recently, an alternative selecꢀ
tivity control was exploited, in which the approach of organoꢀ
metallic entities was efficiently controlled by coordination
with a suitable functional group (i.e., directed addition). Two
different modes of this reaction have been demonstrated to
date. Mode I (Scheme 1) involves a diastereoselective addiꢀ
tion directed by a suitable functionality (typically an alcohol
function) tethered to C1 of cyclopropene.6 Mode II includes
the processes in which the facial selectivity of carbometallaꢀ
tion is governed by a directing group at Cꢀ3. Suitable directꢀ
ing functionalities successfully employed in these transforꢀ
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Scheme 2
Scheme 3
Scheme 4
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The Journal of Organic Chemistry
RESULTS AND DISCUSSION
triggered a strain releaseꢀdriven cleavage of the small ring in
1
intermediate 4, affording δꢀketoamides 5 (Scheme 2). Having
Carbomagnesiation of prochiral cyclopropenes was first
probed on the benchmark substrate methyl 1ꢀphenylcyclopropꢀ
2ꢀeneꢀ1ꢀcarboxylate (6a). Fox has previously demonstrated the
diastereoselective carbozincation, followed by electrophilic
trapping, of 6 and several related esters to obtain the correꢀ
sponding cyclopropylzinc species 7. Methylated cyclopropane
8, as well as ethyl and phenyl analogs were obtained in high
yield and diastereoselectivity (Scheme 3).8c Analysis of literaꢀ
ture data showed that most of the directed carbomagnesiations
of cyclopropenes were carried out in the presence of excess
Grignard reagents (up to 4 equiv.) and at least 20 mol% of
copper(I)
developed several convenient preparative approaches to
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6
7
8
9
prochiral
1ꢀalkylꢀN,Nꢀdimethylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxamides,13 we envisioned them as very attractive
synthons for synthesis of nonꢀracemic cyclopropanes via
asymmetric carbometallation reactions. The amide functionaliꢀ
ty has previously proved efficient as an activating and/or diꢀ
recting group in baseꢀassisted addition of oxygenꢀ and nitroꢀ
gen based nucleophiles,14 as well as in transition metalꢀ
catalyzed hydrometallation reactions of cyclopropenes;
providing excellent diasteroselectivities in alltested transforꢀ
mations.15 Herein, we exploit these substrates in directed carꢀ
bomagnesiation reactions to assess the facial selectivity of
addition with respect to parent esters, as well as the effect of
sterics and the scope of compatible electrophilic reagents.
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Table 1. Optimization of reaction conditions for carbomagnesiation of cyclopropeneꢀ3ꢀcarboxamide 11a
Catalyst, (mol%)
MeMgBr
Solvent
Temperature,
oC
Time, min Yield, %a
drb
1
CuI (20)
1.5 equiv.
Et2O
ꢀ35
30
25
76
78
89
87
89
86
63
<2
13
90
99
0
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
ND
2
60
3
120
60
4
2.0 equiv.
3.0 equiv.
2.0 equiv.
5
6
CuI (10)
CuI (5)
CuI (2.5)
none
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
CuI (5)
MTBE
THF
>99:1
>99:1
>99:1
ND
DME
NiCl2 (10)
CoCl2 (10)
FeBr2 (10)
MnCl2 (10)
V(O)(acac)2 (10)
Ti(Cp)2Cl2 (10)
CuCN (5)
36
40
<2
<2
<2
74
64
13
98
58
97
96
94
96
95
>99:1
>99:1
ND
ND
ND
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
CuBr (5)
CuCl (5)
CuCl2 (10)
CuI (5)
20
0
30
15
5
1.35 equiv.
a) NMR yields of crude reaction mixtures using dibromomethane as the internal standard.
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b) Diastereomeric ratios (cis:trans) were determined by NMR analysis of crude reaction mixtures. >99:1 ratios are reported for all
cases when the minor diastereomer was not detected. Note “ND” indicates that the ratios were not determined due to very low
yield of product.
1
2
3
4
5
6
7
8
9
catalyst (typically CuI or CuCN) in ether at temperatures beꢀ
preꢀmix the Grignard reagent with CuI to generate Gilman
cuprate, and then add the solution of cyclopropene slowly to
this mixture. As a result, a mixture of diastereomeric esters (8
and 2ꢀepiꢀ8) was obtained with low selectivity (Scheme 3).
o
low ꢀ20 C.7ꢀ12 In line with these previous findings, the reacꢀ
tion of ester 6 with excess MeMgBr (9a) in ether carried out at
o
higher temperatures (0 C and above) in the presence of 20
mol% CuI did not provide the desired product 8, due to a conꢀ
current attack of the Grignard reagent at the ester moiety to
produce a tertiary alcohol. In contrast, the same reaction carꢀ
The disappointing result provided by cyclopropenyl ester 6
was not surprising in view of relatively low coordinating abilꢀ
ity of ester function. Accordingly, expectations were held
high for cyclopropeneꢀ3ꢀcarboxamides 1113 (Scheme 4), with
their increased tolerance toward Grignard reagents and strongꢀ
er coordinating ability to Lewis acidic magnesium atom. The
latter
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o
ried out below ꢀ60 C did not proceed at all, returning starting
material 6. After optimization, it was found that carbomagneꢀ
siation of 6 was the most productive when carried out for 20
o
min between ꢀ45 and ꢀ35 C, and quenched with aqueous amꢀ
o
monia at <ꢀ20 C (Scheme 3). Interestingly, this reaction did
not proceed at all when MeMgBr was added to the stirred soꢀ
lution of cyclopropene and copper catalyst. It was essential to
Table 2. Carbomagnesiation of cyclopropeneꢀ3ꢀcarboxamides with various Grignard reagents
Yield, %a
96 (A)
83 (B)
90 (B)
93 (A)
97 (A)
94 (A)
84 (A)
10c
drb
11
R1
R2
9
R3
15
1
Et
Et
Me
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
20:1
11a
11a
11a
11a
11a
11a
11a
11a
11b
11b
11b
11c
11c
11c
11d
11d
11d
11e
11e
11e
11f
11f
11f
11g
11g
11g
11h
11i
9a
9b
9c
9d
9e
9f
15aa
15ab
15ac
15ad
15ae
15af
15ag
15ah
15ba
15bd
15be
15ca
15cd
15ce
15da
15dd
15de
15ea
15ed
15ee
15fa
15fd
15fe
15ga
15gd
15ge
15ha
2
Et
3
iꢀBu
4
Ph
5
CH=CH2
CH2CH=CH2
CH2SiMe3
C≡CꢀPh
Me
6
7
9g
9h
9a
9d
9e
9a
9d
9e
9a
9d
9e
9a
9d
9e
9a
9d
9e
9a
9d
9e
9a
9a
9a
8
9
iꢀPr
iꢀPr
94 (A)
91 (A)
88 (A)
95 (A)
93 (A)
84 (A)
91 (A)
87 (A)
82 (A)
90 (A)
89 (A)
86 (A)
92 (A)
81 (A)
83 (A)
94 (A)
95 (A)
80 (A)
90 (A)
NRd
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11
12
13
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15
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19
20
21
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29
Ph
CH=CH2
Me
>99:1
>99:1
13:1
Bn
Bn
Ph
CH=CH2
Me
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
9:1
ꢀ(CH2)4ꢀ
ꢀ(CH2)5ꢀ
ꢀ(CH2)2O(CH2)2ꢀ
CH2CH=CH2
Ph
CH=CH2
Me
Ph
CH=CH2
Me
Ph
CH=CH2
Me
CH2CH=CH2
Ph
CH=CH2
Me
>99:1
>99:1
Me
H
MeO
H
H
nꢀBu
NRd
11j
a) Isolated yields of purified products. Reactions were carried out at 0 oC for 5 min or at ꢀ45 oC for 60 min according to methods A
and B, respectively.
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b) Diastereomeric ratios (cis:trans) were determined by 1H NMR analysis of crude reaction mixtures. Ratios of >99:1 are reported
in all cases when the minor diastereomer was not detected.
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2
3
4
5
6
7
8
9
o
c) PhꢀC≡CMgBr was prepared in situ by stirring MeMgBr with excess phenylacetylene for 1 h at 55 C. The reaction with cycloꢀ
propene was then carried out for 60 min at 0 oC.
d) Starting cyclopropenes were returned intact.
o
would lead to better stabilization of coordination complex 12,
ether at ꢀ35 C (Table 1, entries 1ꢀ3). To our delight, the deꢀ
sired carbomagnesiation proceeded with perfect diastereoseꢀ
lectivity, albeit rather sluggishly; with only 25% of product
15aa formed in first30 min (entry 1). The conversion imꢀ
proved slightly within the next half hour (entry 2), after which
time the reaction has practically stopped, with no significant
progress observed upon further stirring (entry 3). To give the
reaction a boost, we increased the concentration of the Griꢀ
gnard reagent, which resulted in no improvement (entries 4ꢀ5).
Interestingly, reducing
as well as the key cyclopropylmagnesium intermediate 13,
thus ensuring a better overall diastereoselectivity of the proꢀ
cess. Finally, since the amide function has reduced anionꢀ
stabilizing ability, intermediate 13 was expected to have much
lower propensity towards ring cleavage to produce olefin byꢀ
products 14, which were abundant in the carbometallation of
parent esters.8b,16
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With these considerations in mind, we subjected a solution
of amide 11a to the preꢀmixed Gilman reagent generated from
20 mol% of CuI and 1.5 equiv. of MeMgBr (9a) in diethyl
Scheme 5
Scheme 6
the amount of copper down to 5% did not affect the reaction
rate (entries 6ꢀ7); however, further decrease of the catalyst
load dropped the efficiency of carbomagnesiation (entry 8),
which in the absence of metal did not proceed at all (entry 9).
Screening of several most common ethereal solvents showed
good conversion for all but methyl tertꢀbutyl ether (MTBE,
using copper(I) iodide. An attempt to carry out carbomagneꢀ
siation at room temperature resulted in dramatic reduction of
the yield (entry 23), mainly due to formation of resins. It was
discovered, however, that the reaction proceeded much faster
at 0 oC in a span of 5 min without significant loss of the overꢀ
all efficiency (entries 24ꢀ27). These milder conditions also
allowed for cutting down the excess Grignard reagent to only
1.35 equiv. (entry 28). Carbomagnesiation performed in a
preparative scale (method A, see Experimental Part for details)
afforded cyclopropane 15aa in 96% isolated yield (Table 2,
entry 1).
entry 10).
The best results were obtained using 1,2ꢀ
dimethoxyethane (DME), in which nearly quantitative yield of
15aa was obtained after 1 hour, with perfect diastereoselecꢀ
tivity (entry 12). Next, we evaluated different copper salts and
other related metal catalysts. Most of the tested transition
metals were no match for copper (Table 1, entries 13ꢀ18).
Marginal catalytic activity was observed for cobalt(II) (entry
14) and iron(II) (entry 15), whereas reactions using other metꢀ
als afforded no product at all. Catalytic performance of copꢀ
per(I) salts decreased in the series CuI > CuCN > CuBr >
CuCl. This trend is collinear with the solubility of these salts
in ethereal solvents which, in turn, affects the formation of the
reactive cuprate species. Surprisingly good results were obꢀ
tained in the presence of catalytic amounts of copper(II) chloꢀ
ride (entry 22), which, apparently, was reduced in situ into
copper(I). However, the Cu(II) salt was eliminated due to its
moistureꢀsensitive nature, and all further work was performed
With optimized conditions for addition of MeMgBr in hand,
we tested the reactivity of cyclopropeneꢀ3ꢀcarboxamide 11a
towards other Grignard reagents. Interestingly, use of EtMgBr
o
(9b) under conditions of method A (at 0 C) resulted in ring
opening affording hexꢀ3ꢀenamide 16aa as a sole product in
77% yield (Scheme 5). Similar results were obtained in the
reaction involving iꢀBuMgBr (9c), except the corresponding
enamide 16ac was produced as an inseparable mixture with
normal cyclopropane product 15ac, and thus was not isolated
in individual form (Scheme 5). We reasoned that this problem
can be alleviated by decreasing the reaction temperature and
extending the time to achieve full conversion (this protocol is
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reported as Method B, see Experimental Part for details). Acꢀ of a wide variety of amides, including bulky N,Nꢀdiisopropyl
1
2
3
4
5
6
7
8
cordingly, both Grignard reagents 9b and 9c were added to
cyclopropene 11a at ꢀ45 oC affording the corresponding alkylꢀ
ated cyclopropanes 15ab and 15ac in high yield (Table 2, enꢀ
tries 2ꢀ3). All other Grignard reagents tested in the carbomagꢀ
nesiation of 11a did not show any signs of ring opening under
conditions of Method A, allowing for fast and diastereoselecꢀ
tive addition of phenyl (15ad), vinyl (15ae), allyl (15af), and
trimethylsilylmethyl (15ag) moieties in the threeꢀmembered
rings (entries 4ꢀ7). Our attempts to add magnesium acetyꢀ
lenide species 9h resulted in a very sluggish reaction. Both
reactants remained essentially intact under the standard reacꢀ
tion conditions, affording disappointedly low yield of the couꢀ
pling product 15ah (entry 8). It should be mentioned that ring
retentive addition of metal acetylenides to cyclopropenes has
always posed a challenge.5b,7a,17
amide 11b (Table 2, entries 9ꢀ11), potentially deprotectable
N,Nꢀdibenzylamide 11c (entries 12ꢀ14), and N,Nꢀdiallylamide
11g (entires 24ꢀ26), as well as derivatives of pyrrolidine (11d,
entries 15ꢀ17), pyrimidine (11e, entries 18ꢀ20), and morphoꢀ
line (11f, entries 21ꢀ23) was very efficient and yielded a single
o
product under conditions of method A (5 min at 0 C). In a
few cases addition of PhMgBr (9d) was somewhat less selecꢀ
tive (entries 10, 13, 25). Typically, crude material obtained
after aqueous work up and extraction of the reaction mixture
was of sufficient purity for any practical synthetic application.
For analytical purposes, all products were additionally purified
by column chromatography.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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35
36
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43
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Reaction of Wienreb amide 11h with MeMgBr under condiꢀ
tions of method A proceeded highly chemoꢀ and stereoselecꢀ
tively, affording the corresponding adduct 15ha with preꢀ
served amide function (Table 2, entry 27). However, carrying
out this transformation in the presence of excess Grignard
reagent at 40
We have also explored the relative reactivity of tertiary cyꢀ
clopropeneꢀ3ꢀcarboxamide derivatives bearing various substitꢀ
uents at nitrogen atom with benchmark Grignard reagents 9a,
9d, and 9e. We were pleased to find that carbomagnesiation
Table 3. Probing of different electrophilic reagents in the directed carbomagnesiation of cyclopropeneꢀ3ꢀcarboxamides
Yield, %a
drb
11
R1, R2
9
R3
EX
Product
18aa
18ae
19aa
19be
19ed
20aa
20fd
1
2
3
4
5
6
7
8
Et, Et
Me
MeOD
98
86
86
81
87
87
87
76
>99:1
>99:1
>99:1
7:1
11a
11a
11a
11b
11e
11a
11f
11g
9a
9e
9a
9e
9d
9a
9d
9e
CH=CH2
Me
MeI
iꢀPr, iꢀPr
CH=CH2
Ph
ꢀ(CH2)4ꢀ
>99:1
>99:1
>99:1
>99:1
Et, Et
Me
CH2=CHCH2Br
ꢀ(CH2)2O(CH2)2ꢀ
Ph
CH2CH=CH2,
CH2CH=CH2
CH=CH2
20ge
9
Et, Et
Me
PhCH2Br
82
79
80
72
79
52
80
63
51
60
80
88
79
83
>99:1
15:1
11a
11c
11d
11a
11a
11c
11d
11a
11c
11a
11a
11a
11a
11a
9a
9d
9e
9a
9a
9e
9d
9a
9e
9a
9d
9d
9a
9d
21aa
21cd
21de
22aa
23aa
23ce
23dd
24aa
24ae
25aa
25ad
26ad
27aa
27ad
10
11
12
13
14
15
16
17
18
19
20
21
22
Bn, Bn
ꢀ(CH2)3ꢀ
Et, Et
Ph
CH=CH2
Me
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
92:8c
96:4c
93:7c
>98:2
>99:1
Me3SiCl
EtCOCl
Bn, Bn
ꢀ(CH2)3ꢀ
Et, Et
CH=CH2
Ph
Me
I2
Bn, Bn
Et, Et
CH=CH2
Me
PhCHO
Ph
4ꢀFC6H4CHO
Me
Ph
tꢀBuCHO
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The Journal of Organic Chemistry
23
24
CH2SiMe3
Me
79
82
>99:1
>98:2
11a
11h
9g
9a
27ag
27ha
1
2
3
4
5
6
7
8
a) Isolated yields of purified products. Deuterium purity for compounds 18aa and 18ae was 92ꢀ94% (measured by 1H NMR).
b) Diastereomeric ratios (cis:trans) were determined by 1H NMR analysis of crude reaction mixtures. Ratios of >99:1 are reported
in all cases when the minor diastereomer was not detected.
c) Listed are dr’s of epimers at the tertiary alcohol stereogenic center. Facial selectivity of carbomagnesiation was >99:1 in all theꢀ
se examples.
oC for an extended period of time allowed for nucleophilic
attack at both electrophilic moieties to give ketone 17 in good
yield as a sole product (Scheme 6).
propenes 11aꢀc,f,g were subjected to copperꢀcatalyzed meꢀ
thylꢀ, phenylꢀ, or vinylmagnesiation followed by treatment
with an SN2ꢀactivealkyl halide, such as methyl iodide, allyl
bromide, or benzyl bromide. In all but one examples, cis,cisꢀ
adducts 19, 20 and 21 were obtained as sole products in high
yield (entries 3ꢀ4, 6ꢀ11). This configuration was unambiguꢀ
ously confirmed by single crystal Xꢀray crystallography of
product 19ed (Figure 1). Notable deterioration of the diaꢀ
stereoselectivity (down to 7:1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It should also be mentioned that this copperꢀcatalyzed carꢀ
bomagnesiation reaction is applicable to tertiary amides only,
and all our attempts to engage primary (11i) and secondary
(11j) analogs in this transformation resulted in recovery of
starting materials (Table 2, entries 28ꢀ29).
Having explored the scope of substrates, we next looked inꢀ
to a possibility to introduce an additional substituent in the
cyclopropyl ring by intercepting the intermediate cyclopropyl
anion with a suitable electrophilic species. To this end, cycloꢀ
Scheme 7
Figure 2. ORTEP drawing of crystal structure of product 25aa
(major diastereomer) showing atomꢀlabeling scheme and 50%
probability thermal ellipsoids. Only one population of disordered
of NꢀEt group is shown for clarity – See Supporting Information
for details.
Figure 1. ORTEP drawing of crystal structure of compound
19ed (major diastereomer) showing atomꢀlabeling scheme and
50% probability thermal ellipsoids. Only one population of disorꢀ
dered molecules is shown for clarity – See Supporting Inforꢀ
mation for details.
was observed only in the case of a very bulky N,Nꢀ
diisopropylamide group (Table 3, entry 4). Furthermore, N,Nꢀ
diethylꢀ1ꢀmethylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11k) bearꢀ
7
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ing methyl substituent at cyclopropene sp3ꢀhybridized carbon
Page 8 of 29
in both cases occurred selectively in cisꢀfashion, with the isoꢀ
1
2
3
4
5
6
7
8
atom next to the amide function underwent smooth reaction
under the typical conditions, affording product 21ka in high
yield (Scheme 8).
topic purity of 92ꢀ94%.
We were also intrigued by the idea of employing aldehydes
as the electrophiles in this transformation to obtain cycloꢀ
propylmethanol derivatives 25ꢀ27 bearing an additional stereꢀ
ogenic center at the hydroxyl group. This approach, while
known for almost 40 years, typically suffers from poor diaꢀ
stereoselectivity when a chiral cyclopropylmetal reagent is
added to a prochiral aldehyde, normally affording a nearly
equimolar mixture of two isomers.18 Prior attempts to enforce
the selectivity through intramolecular coordination of the cyꢀ
clopropylmagnesium species with an appropriate Lewis base,
resulted in modest diastereoselectivity of ~2:1.12 Marek has
shown an elegant alternative route through employment of
sterically hindered acylsilanes in place of aldehydes. Comꢀ
bined with protiodesilation, this method allowed for a much
more selective synthesis of cyclopropylmethyl alcohols, with
dr’s ranging from 91:9 to 95:5.12 We hoped that the profound
templating effect of the amides would allow for superior conꢀ
trol of the diastereoselectivity in the direct reaction with aldeꢀ
hydes. To probe this idea, we carried out carbomagnesiation
of cyclopropene 11a with
Electrophilic trapping with trimethylsilyl chloride was also
successful, providing the corresponding silylcyclopropane
22aa (entry 12). We found, however, that silyl electrophiles
are compatible only with methylmagnesiation reaction. Atꢀ
tempts to couple silylation with phenylꢀ or vinylmagnesiation
of 11a resulted in protonated products 15ad and 15ae, respecꢀ
tively. Electrophilic trapping of cyclopropylmetal species
with acyl chlorides was also probed to access cyclopropyl
ketones. Acyl chlorides must be freshly distilled and free of
acid to avoid competitive protonolysis of cyclopropyl magneꢀ
sium intermediate. Due to significant steric bulk, the secondꢀ
fold addition of cyclopropylmetal species to carbonyl group
did not pose a problem, and the corresponding ketones 23
were isolated in reasonable yields and with excellent cisꢀ
selectivity (entries 13ꢀ15). Trapping with iodine also proceedꢀ
ed smoothly affording stereochemically defined cyclopropyl
iodides (entries 16, 17). We have also tested methanolꢀd
quench to obtain deuteriumꢀlabeled cyclopropanes 18aa and
18ae (Table 3, entries 1ꢀ2). Incorporation of deuterium label
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8
Scheme 9
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
methylmagnesium bromide (9a) and treated the resulting mixꢀ
gents formed are chiral and racemic, one can envision forꢀ
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ture with benzaldehyde. The target cyclopropylmethanol 25aa
was indeed obtained in good yield and with respectable diaꢀ
stereoselectivity of 92:8 (Table 3, entry 18). A bulky cycloꢀ
propylmetal species generated from 11a upon treatment with
phenylmagnesium bromide (9d) afforded the corresponding
products 25ad and 26ad in excellent yields and high dr’s (enꢀ
tries 19ꢀ20). When pivalaldehyde was used as the electroꢀ
phile, single diastereomers were produced regardless of the
nuceleophilic component employed (Table 3, entries 21ꢀ24).
Also, compatibility of Winereb amide function in substrate
11h was demonstrated, allowing for preparation of alcohol
27ha as a single diastereomer (entry 24). Winereb amide
27ha was then used to establish the relative configuration of
stereogenic centers in the products. Acidꢀcatalyzed hydrolysis
of the amide moiety was accompanied with spontaneous cyꢀ
clization to furnish bicyclic lactone 28 (Scheme 7), in which
cisꢀ relationꢀ ship of tertꢀbutyl substituent at Cꢀ4 and bridgeꢀ
head hydrogen at Cꢀ5 was confirmed by 2DꢀNOESY experiꢀ
ment.19 Independently, the relative configuration of adduct
25aa was unambiguously confirmed by single crystal Xꢀray
diffraction (Figure 2). Evidently, this stereochemistry resulted
from an effective chelation of electrophilic aldehyde with
Lewisꢀacidic magnesium atom. Typically, the addition of
Grignard reagents to a carbonyl group is believed to proceed
via a sixꢀmembered transition states, involving two molecules
of organylmagnesium species. Since in our case these reaꢀ
mation of two types of diastereomeric dimers, with C2ꢀ
symmetric (complexes 29 and 31) or Ciꢀsymmetric (complexes
30 and 32) arrangement organyl ligands around halogenꢀ
bridged bisꢀmagenesium clusters, respectively (Scheme 8). It
should be pointed out, that the R3 group installed upon addiꢀ
tion of a Grignard reagent to cyclopropene, blocks the apꢀ
proach to the Reꢀface of the electrophile due to unfavorable
steric interaction with group R4, rendering coordination comꢀ
plexes 31 and 32 highly unfavorable (Scheme 8) and leaving
the Siꢀface attack as the only available option (complexes 29
and 30). Hence, (R*,R*,S*,R*)ꢀ33 is formed in small quantiꢀ
ties or not observed at all; while diastereomers 25ꢀ27 with
(R*,R*,S*,S*)ꢀconfiguration are afforded as major or the only
products (Scheme 8).
To fully understand the effect of the steric factors, we also
tested carbomagnesiation of cyclopropenylcarboxamides 38
bearing a substituent at the double bond, easily available via
the Rhꢀcatalyzed cyclopropenation of terminal alkynes 35
(Scheme 9).20 Several studies of directed or nonꢀdirected addiꢀ
tion of organometallic species to cyclopropenes bearing a subꢀ
stituent at the double bond have been reported.21 In all these
contributions, the regioselectivity of addition was governed by
electronic factors, resulting in geminallyꢀsubstituted products,
with the organyl group being added to the more substituted
olefin carbon.
Table 4. Reverse of the Regioselectivity in the AmideꢀDirected Catalytic Carbomagnesiation of Cyclopropenes 38 with Substiꢀ
tuted Double Bond
R5
Producta
41aa
drc
38
9
R3
EX
Yield,
42:41
b
%
1
n-Bu
Me
NH4Cl
90
>98:2
12:88
38a
9a
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2
CH=CH2
Ph
(E = H)
88
91
75
92
89
84
70
97
99
52
93
91
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
19:81
70:30
75:25
91:9
38a
38a
38a
38b
38b
38b
38b
38c
38d
38e
38f
9e
9d
9g
9a
9d
9e
9g
9a
9a
9a
9a
9a
41ae
42ad
42ag
42ba
42bd
42be
42bg
42ca
42da
42ea
42fa
42bh
1
2
3
4
5
6
7
8
3
4
CH2SiMe3
Me
5
Ph
6
Ph
>98:2
>98:2
>98:2
86:14
95:5
7
CH=CH2
CH2SiMe3
Me
8
9
4ꢀMeC6H4
4ꢀFC6H4
4ꢀMeOC6H4
4ꢀCF3C6H4
Ph
9
10
11
12
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
90:10
>98:2
N/Ad
Me
MeI
38b
(E = Me)
a) Major regioisomer is shown.
b) Combined yield of purified product isolated as a mixture of regioisomers 41 and 42.
c) Facial selectivity measured by 1H NMR and/or GC analysis of crude reaction mixtures. >98:2 indicates the minor diastereomers
were not detected.
d) Products 41bh and 42bh are indistinguishable, since R3 = E in this case.
O
O
Ph
Ph
NR2
NR2
vs
EDG
EWG
Cu(III)
R2
R2
Cu(III)
R2
R2
43
44
Figure 3. Electronic control of regioselectivity in cuprate addition to cyclopropenes
The opposite regioselectivity resulting from an overwhelming
sterics created by an extremely bulky bisꢀ(tertꢀ
butyl)magnesium reagent was shown on a single example and
required relatively harsh conditions causing partial cleavage of
the cyclopropyl ring.22 We reasoned that strong coordination
of the organometallic moiety to a sterically demanding carꢀ
boxamide group would amplify the effect of steric factors and
divert the regioselectivity of carbomagnesiation toward preꢀ
dominant formation of the alternate cyclopropylmetal species
40 (Scheme for Table 4). To test this idea, we treated nꢀ
butylsubstituted cyclopropeneꢀ3ꢀcarboxamide 38a with variꢀ
ous Grignard reagents. It was found that compact methylꢀ
magnesium bromide (9a) gave a nonꢀselective reaction, mostꢀ
ly providing the “normal” carbomagnesiation product 41aa
accompanied by small amounts of regioisomer 42aa (Table 4,
entry 1). Similar results were obtained in the reaction of anꢀ
other nonꢀbulky Grignard reagent, vinylmagnesium bromide
(9e) (entry 2). A notable reversal of the regiochemistry was
observed with more sterically demanding PhMgBr (9d) and
Me3SiCH2MgBr (9g), which gave rise to 42ad and 42ag as the
the major products (entries 3, 4). The profound effect of steric
factors was even more evident in carbomagnesiation of 1ꢀ
arylsubstituted cyclopropenes 38b-f (entries 5ꢀ13). Thus, a
respectable diastereomeric ratio of 91:1 was observed in the
reaction of 38b with MeMgBr reagent (entry 5), while all othꢀ
er Grignard reagents tested exclusively provided adducts
42bd, 42be, 42bg (entries 6ꢀ8). We next looked at the effect
of electronic factors on the regiochemistry of this directed
addition. To this end, cyclopropenes 38cꢀf bearing aryl subꢀ
stituents with different electronic properties were synthesized
from the corresponding arylacetylenes 35cꢀf (Scheme 9) and
then subjected to the directed copperꢀcatalyzed carbomagneꢀ
siation with MeMgBr (9a). In line with our expectations illusꢀ
trated below in Figure 3, there was a significant improvement
of the regioselectivity in reactions of electron poor substrates
38d and 38f as compared to more electron rich analogs 38c
and 38e (Table 4, entries 9ꢀ12). A sterically controlled nucleoꢀ
philic attack of the cuprate induces polarization of the double
bond causing a negative charge build up on the carbon adjaꢀ
cent to the aromatic substituent. In this situation, the presence
of an electronꢀwithdrawing group helps stabilize intermediate
43 as opposed to 44 (Figure 3).
Finally, a possibility to trap the anionic intermediate with an
electrophile other than proton was probed by intercepting
methylmagnesiation reaction of cyclopropene 38b with MeI.
In a single reaction tested, a pentasubstituted cyclopropane
42bh was isolated as a sole product in high yield (Table 4,
entry 13). Further studies of this approach, including installaꢀ
tion of nonꢀsymmetric substituents with simultaneous control
of regioꢀ and diastereoselectivity is currently underway in our
laboratories.
CONCLUSION
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The Journal of Organic Chemistry
In conclusion, an efficient synthetic protocol for the copperꢀ
gel column chromatography eluting with a mixture of hexane
and ethyl acetate (6:1). The titled compound was obtained as
a pale yellow solid, mp 73.1 – 75.9 oC, Rf 0.26. Yield 761 mg
(2.88 mmol, 50%). 1H NMR (500 MHz, CDCl3) δ 7.57 – 7.53
(m, 2H), 7.44 – 7.40 (m, 2H), 7.33 – 7.28 (m, 2H), 7.27 – 7.20
(m, 3H), 7.16 (s, 1H), 3.74 (s, 3H), 2.40 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 175.3, 141.2, 140.5, 130.0 (+, 2C), 129.7
(+, 2C), 128.3 (+, 2C), 128.1 (+, 2C), 126.5 (+), 122.7, 117.1,
99.2 (+), 52.2 (+), 33.5, 21.7 (+); FTIR (KBr, cmꢀ1): 3025,
2948, 1719, 1504, 1433, 1210, 1020, 820, 699; HRMS (TOF
ES): Found 287.1053, calculated for C18H16O2Na (M+Na)
287.1048 (1.7 ppm).
1
2
3
4
5
6
7
8
catalyzed, directed carbomagnesiation of cyclopropeneꢀ3ꢀ
carboxamides was developed. It was demonstrated that the
carboxamide group at Cꢀ3 serves as a superior directing group
for this reaction permitting a very effective control of diaꢀ
stereoselectivity. The use of cyclopropenylcarboxamides also
allows for a wide range of Grignard reagents to be employed
in carbomagnesiation of the smallest cyclic olefins, in comꢀ
plement to the carbozincation reaction, which requires often
less readily available organozinc reagents. Successful trapꢀ
ping of cyclopropylmagnesium species with various electroꢀ
philic reagents showcased the synthetic application of the deꢀ
scribed transformation. High degree of diastereoselectivity
control achieved in the reaction with aldehydes allowed for
preparation of cyclopropylmethanols bearing four contiguous
stereogenic centers (in racemic form). Steric and electronic
factors affecting the regioselectivity of carbomagnesiation of
Cꢀ1 substituted cyclopropenes were also analyzed.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2-(4-fluorophenyl)-1-phenylcycloprop-2-ene-1-
carboxylate (36d): This material was obtained according to
the protocol described above for the synthesis of compound
36c starting from 1ꢀethynylꢀ4ꢀfluorobenzene (35d) (1.0 g, 8.32
mmol, 1.5 equiv.), rhodium(II) acetate dimer (25.0 mg, 0.111
mmol, 0.02 equiv.) and methyl 2ꢀdiazoꢀ2ꢀphenylacetate (34)
(977 mg, 5.55 mmol, 1.0 equiv.). The reaction mixture was
then evaporated and purified by using 6:1 mobile phase.
Crude product was purified by preparative column chromatogꢀ
raphy on silica gel eluting with a mixture of hexane/EtOAc
(6:1). The titled compound was obtained isolated as amorꢀ
phous solid, Rf 0.26. Yield 1.21 g (4.51 mmol, 81% yield).
1H NMR (500 MHz, CDCl3) δ 7.66 – 7.60 (m, 2H), 7.42 –
7.36 (m, 2H), 7.34 – 7.28 (m, 2H), 7.26 – 7.21 (m, 1H), 7.20
(s, 1H), 7.17 – 7.10 (m, 2H), 3.73 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 174.9, 163.6 (d, J = 251.0 Hz), 140.7, 131.9
(+, d, J = 9.0 Hz, 2C), 128.2 (+, 2C), 128.1 (+, 2C), 126.6 (+),
121.8 (d, J = 3.5 Hz), 116.5, 116.2 (+, d, J = 21.9 Hz, 2C),
99.8 (+, d, J = 2.7 Hz), 52.3 (+), 33.7; 19F NMR (376 MHz,
CDCl3) δ ꢀ109.1 (s, 1F); FTIR (KBr, cmꢀ1): 2951, 1723, 1599,
1503, 1434, 1223, 1014, 840, 699; HRMS (TOF ES): Found
291.0799, calculated for C17H13O2FNa (M+Na) 291.0792 (2.4
ppm).
EXPERIMENTAL PART
General
NMR spectra were recorded on a Bruker Avance DRXꢀ500
(500 MHz) with a dual carbon/proton cryoprobe (CPDUL).
13C NMR spectra were registered with broadband decoupling.
The (+) and (ꢀ) designations represent positive and negative
intensities of signals in 13C DEPTꢀ135 or 1Hꢀ13C HSQC experꢀ
iments. IR spectra were recorded on a ThermoFisher Niꢀ
colet™ iS™ 5 FTꢀIR Spectrometer. HRMS was carried out
on LCT Premier (Micromass Technologies) instrument emꢀ
ploying ESI TOF detection techniques. Glassware used in
moistureꢀfree syntheses was flameꢀdried in vacuum prior to
use. Column chromatography was carried out on silica gel
(Sorbent Technologies, 40ꢀ63 mm). Preꢀcoated silica gel
plates (Sorbent Technologies Silica XG 200 mm) were used
for TLC analyses. Anhydrous dichloromethane was obtained
by passing degassed commercially available HPLCꢀgrade
inhibitorꢀfree solvent consecutively through two columns
filled with activated alumina and stored over molecular sieves
under nitrogen. Water was purified by dual stage deionization
followed by dual stage reverse osmosis. Anhydrous THF and
DME were obtained by refluxing commercially available solꢀ
vents over calcium hydride followed by distillation in a stream
of dry nitrogen. All other reagents and solvents were purꢀ
chased from commercial vendors and used as received. Prepaꢀ
ration of cyclopropenes 11aꢀj, 38a-b was described in details
in our previously published report and their physical and specꢀ
tral data are also described therein.13b Cyclopropene 11k was
obtained via 1,2ꢀdehydrobromination of the corresponding
bromocyclopropane according to the previously published
procedure.23 Syntheses of cyclopropenes 38cꢀf is described
below.
1-Phenyl-2-(p-tolyl)cycloprop-2-ene-1-carboxylic
acid
(37c): A solution of methyl 1ꢀphenylꢀ2ꢀ(pꢀtolyl)cyclopropꢀ2ꢀ
eneꢀ1ꢀcarboxylate (36c) (300 mg, 1.13 mmol, 1.0 equiv.) in a
mixture of methanol and tetrahydrofuran (1:1, 20 mL) was
stirred at 0 oC. An aqueous solution of sodium hydroxide (1.5
M, 8 mL, 12 mmol) was added dropwise and the mixture was
stirred for 18 h. Organic solvents were then removed under
reduced pressure and the remaining aqueous solution was addꢀ
ed to dichloromethane (20 mL). The mixture was acidified
with 1N aqueous HCl to pH 2. The organic phase was separatꢀ
ed and the aqueous layer was extracted with dichloromethane
(3 x 10 mL). The combined organic phases were washed with
brine, dried with MgSO4, filtered, and concentrated. The obꢀ
tained product was pure enough to be used in further amide
coupling as is, however, if necessary, further purification can
be achieved by column chromatography on silica gel eluting
with a mixture of hexane and EtOAc (3:1). The titled comꢀ
pound was obtained as a colorless solid, mp 134.5 – 135.9 oC,
Rf 0.19. Yield 261 mg, 1.04 mmol, 92%). 1H NMR (500
MHz, CDCl3) δ 7.56 – 7.51 (m, 2H), 7.45 – 7.39 (m, 2H), 7.30
– 7.26 (m, 2H), 7.26 – 7.18 (m, 3H), 7.13 (s, 1H), 2.39 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 181.3, 140.7, 140.4, 130.1 (+,
2C), 129.8 (+, 2C), 128.5 (+, 2C), 128.1 (+, 2C), 126.7 (+),
122.4, 116.7, 98.7 (+), 33.2, 21.7 (+); FT IR (KBr, cmꢀ1):
3137, 3025, 1684, 1408, 1224, 1173, 819, 698; HRMS (TOF
ES): Found 251.1075, calculated for C17H15O2 (M+H)
251.1072 (1.2 ppm).
Preparation of starting materials
Methyl
1-phenyl-2-(p-tolyl)cycloprop-2-ene-1-
carboxylate (36c): 25 mL 2ꢀneck flask was charged with pꢀ
tolylacetylene (35c) (1.0 g, 8.61 mmol, 1.5 equiv.), rhodiꢀ
um(II) acetate dimer (25.0 mg, 0.115 mmol, 0.02 equiv.), and
7 mL dichloromethane. The mixture was stirred under inert
nitrogen atmosphere at room temperature, and methyl 2ꢀdiazoꢀ
2ꢀphenylacetate (34) (1.0 g, 5.74 mmol, 1.0 equiv.) in solution
in DCM (5 mL) was added via syringe pump over 18 hours,
and then stirred for an additional 3 h. The reaction mixture
was then evaporated and the residual oil was purified by silica
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Page 12 of 29
hydrous dichloromethane (7 mL) was stirred in a flame dried
1
2
3
4
5
6
7
8
2-(4-Fluorophenyl)-1-phenylcycloprop-2-ene-1-
carboxylic acid (37d): This material was obtained according
to the protocol described above for the synthesis of compound
round bottom flask under nitrogen atmosphere. Oxalyl chloꢀ
ride (126 ꢁL, 187 mg, 1.47 mmol, 1.5 equiv.) was then added
slowly dropwise and the mixture was stirred at room temperaꢀ
ture for 2 h. The solution was then evaporated under reduced
pressure to provide a pale yellow solid material. This material
was dissolved in freshly dried dichloromethane (6.0 ml) and
added dropwise to a solution of diethylamine (202 ꢁL, 143
mg, 2.0 mmol, 2.0 equiv.) and triethylamine (272 ꢁL, 198 mg,
2.0 mmol, 2.0 equiv.) in dry dichloromethane (6.0 ml) stirred a
flame dried two neck round bottom flask under nitrogen atꢀ
mosphere. The reaction mixture was stirred for 18 h and then
partitioned between water and dichloromethane. The aqueous
phase was then acidified using 1N HCl to a pH 2. The organic
phase was then extracted with slightly acidified water (pH 2, 3
x 10 mL). The combined acidic aqueous layers were then back
extracted once with dichloromethane, which was combined
with other organic phases, washed with brine, dried, filtered,
and concentrated. The crude product was then purified by
silica gel column chromatography eluting with a mixture of
hexane and ethyl acetate (3:1) mobile phase to afford the titled
37c
starting
from
methyl
2ꢀ(4ꢀfluorophenyl)ꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxylate (36d) (300 mg, 1.12
mmol, 1.0 equiv.) The obtained product is typically pure
enough to be used in further amide coupling as is, however, if
necessary, further purification can be achieved by column
chromatography on silica gel eluting with a 1:1 hexane:ethyl
acetate mixture. The titled compound was obtained as a colorꢀ
less solid, mp 138.9 – 140.2 oC, Rf 0.26. Yield 257 mg (1.01
mmol, 90%). 1H NMR (500 MHz, CDCl3) δ 7.64 – 7.59 (m,
2H), 7.41 – 7.37 (m, 2H), 7.31 – 7.27 (m, 2H), 7.24 – 7.19 (m,
1H), 7.18 (s, 1H), 7.15 – 7.09 (m, 2H); 13C NMR (126 MHz,
CDCl3) δ 179.8, 163.8 (d, J = 251.6 Hz), 139.9, 132.1 (+, d, J
= 9.0 Hz, 2C), 128.4 (+, 2C), 128.3 (+, 2C), 127.0 (+), 121.5
(d, J = 2.9 Hz), 116.4 (+, d, J = 21.9 Hz, 2C), 116.3, 99.4 (+,
d, J = 2.9 Hz), 33.3; FTIR (KBr, cmꢀ1): 3138, 3025, 1686,
1599, 1502, 1408, 1227, 837, 698; HRMS (TOF ES): Found
277.0645, calculated for C16H11FO2Na (M+Na) 277.0641 (1.4
ppm).
9
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15
16
17
18
19
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22
23
24
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26
27
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29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
compound as a pale yellow solid, ,p 86.6 – 89.1 C, Rf 0.29.
Yield 299 mg (0.966 mmol, 96%). 1H NMR (500 MHz,
CDCl3) δ 7.82 – 7.70 (m, 2H), 7.32 – 7.27 (m, 2H), 7.26 –
7.22 (m, 2H), 7.22 – 7.17 (m, 1H), 7.05 (s, 1H), 7.05 – 6.99
(m, 2H), 3.56 (dq, J = 14.1, 7.1 Hz, 1H), 3.49 (dq, J = 14.3,
7.2 Hz, 1H), 3.36 – 3.22 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H),
0.95 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
173.2, 163.6 (d, J = 250.7 Hz), 142.4, 132.5 (+, d, J = 8.3 Hz,
2C), 128.6 (+, 2C), 126.4 (+), 126.1 (+, 2C), 122.7 (d, J = 2.9
Hz), 122.0, 115.9 (+, d, J = 21.9 Hz, 2C), 97.7 (+, d, J = 2.7
Hz), 42.2 (ꢀ), 39.0 (ꢀ), 35.5, 13.8 (+), 12.7 (+); 19F NMR (376
MHz, CDCl3) δ ꢀ110.1 (s, 1F); FT IR (KBr, cmꢀ1): 2973,
2934, 1624, 1500, 1428, 1222, 839, 700; HRMS (TOF ES):
Found 332.1426, calculated for C20H20FNONa (M+Na)
332.1427 (0.3 ppm).
N,N-Diethyl-1-phenyl-2-(p-tolyl)cycloprop-2-ene-1-
carboxamide
(38c):
Solution
of
1ꢀphenylꢀ2ꢀ(pꢀ
tolyl)cyclopropꢀ2ꢀeneꢀ1ꢀcarboxylic acid (37c) (250 mg, 1.0
mmol, 1.0 equiv.) and DMF (2 drops) in freshly distilled anꢀ
hydrous dichloromethane (7 mL) was stirred in a flame dried
round bottom flask under nitrogen atmosphere. Oxalyl chloꢀ
ride (130 ꢁL, 190 mg, 1.5 mmol, 1.5 equiv.) was then added
slowly dropwise and stirred at room temperature for 2 h. The
solution was then evaporated under reduced pressure to proꢀ
vide a pale yellow solid material. This material was dissolved
in freshly dried dichloromethane (6.0 mL) and added dropwise
to a solution of diethylamine (206 ꢁL, 146 mg, 2.0 mmol, 2.0
equiv.) and triethylamine (280 ꢁL, 202 mg, 2.0 mmol, 2.0
equiv.), stirred in a flame dried two neck round bottom flask
under an inert nitrogen atmosphere. The reaction mixture was
then stirred for 18 hours and then partitioned between water
and dichloromethane. The aqueous phase was then acidified
using 1N HCl to a pH 2. The organic phase was then extracted
with properly acidified water (pH 2, 3 x 10 mL). The comꢀ
bined acidic aqueous layers were then back extracted once
with dichloromethane which was combined with other organic
layers, washed with brine, dried, filtered, and concentrated.
The product was then purified by silica gel column chromaꢀ
tography eluting with a mixture of hexane and EtOAc (3:1) to
afford the titled compound as a colorless solid, mp 123.3 –
N,N-Diethyl-2-(4-methoxyphenyl)-1-phenylcycloprop-2-
ene-1-carboxamide (38e): Part I. A solution of methyl 2ꢀ(4ꢀ
methoxyphenyl)ꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxylate
(36e)24 (135 mg, 0.482 mmol, 1.0 equiv.) in a 1:1 mixture of
o
methanol and tetrahydrofuran (15 mL) was stirred at 0 C. A
1.5 M aqueous solution of sodium hydroxide (8 mL) was addꢀ
ed dropwise and the mixture was stirred for 18 hours. Organic
solvents were then removed under vacuum and the remaining
aqueous solution was added to dichloromethane (15 mL). The
mixture was acidified to pH 2 with 1N aqueous HCl. The orꢀ
ganic phase was separated and the aqueous layer was extracted
with dichloromethane (3 x 10 mL). The combined organic
phases were washed with brine, dried with MgSO4, filtered,
and concentrated. The crude carboxylic acid 37e was obtained
in 87% yield (112 mg, 0.419 mmol) and was immediately
carried to part II without further purification. Part II. Trimeꢀ
thylamine (83 ꢁL, 59.7 mg, 0.590 mmol, 1.5 equiv.) was addꢀ
o
125.7 C, Rf 0.29. Yield 288 mg (0.943 mmol, 94%). 1H
NMR (500 MHz, CDCl3) δ 7.69 – 7.59 (m, 2H), 7.32 – 7.23
(m, 4H), 7.22 – 7.12 (m, 3H), 7.03 (s, 1H), 3.53 (dq, J = 14.3,
7.1 Hz, 2H), 3.31 (dq, J = 14.0, 7.1 Hz, 2H), 2.33 (s, 3H), 1.19
(t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 173.3, 142.9, 139.9, 130.4 (+, 2C), 129.4 (+,
2C), 128.4 (+, 2C), 126.2 (+), 126.1 (+, 2C), 123.5, 122.1,
97.8 (+), 42.2 (ꢀ), 39.0 (ꢀ), 35.4, 21.7 (+), 13.8 (+), 12.7 (+);
FT IR (KBr, cmꢀ1): 3081, 3023, 2972, 2933, 1625, 1457, 1275,
1118, 820, 700. HRMS (TOF ES): Found 328.1682, calculatꢀ
ed for C21H23NONa (M+Na) 328.1677 (1.5 ppm).
ed
to
2ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxylic acid (37e) (105 mg, 0.390 mmol, 1.0 equiv.) disꢀ
solved in tetrahydrofuran (5 mL). The solution was then
cooled to 0 oC. N,N'ꢀDicyclohexylcarbodiimide (122 mg,
0.590 mmol, 1.5 equiv.), 1ꢀhydroxybenzotriazole hydrate
(80.0 mg, 0.590 mmol, 1.5 equiv.), and diethylamine (52.0 ꢁL,
37.3 mg, 0.51 mmol, 1.3 equiv.) were then added sequentially
and the reaction was allowed to warm to room temperature
over approximately 1 hour before being heated to 42oC and
stirred for 24 hours. Solvent was evaporated and the crude
N,N-Diethyl-2-(4-fluorophenyl)-1-phenylcycloprop-2-
ene-1-carboxamide (38d): Solution of 2ꢀ(4ꢀfluorophenyl)ꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxylic acid (37d) (250 mg, 1.0
mmol, 1.0 equiv.) and DMF (2 drops) in freshly distilled anꢀ
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The Journal of Organic Chemistry
with other organic layers, washed with brine, dried, filtered,
material was purified by silica gel column chromatography
1
2
3
4
5
6
7
8
eluting with 3:1 mixture of hexane and EtOAc to provide the
titled product as a an amber oil, Rf 0.26. Yield 51.7 mg (0.161
mmol, 41%). 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.7
Hz, 2H), 7.30 – 7.26 (m, 2H), 7.26 – 7.23 (m, 2H), 7.20 – 7.14
(m, 1H), 6.94 (s, 1H), 6.87 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H),
3.53 (dq, J = 14.3, 7.1 Hz, 2H), 3.29 (dq, J = 14.0, 7.1 Hz,
2H), 1.19 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 173.4, 160.9, 142.9, 132.1 (+, 2C),
128.5 (+, 2C), 126.2 (+), 126.1 (+, 2C), 122.0, 119.0, 114.2 (+,
2C), 95.9 (+), 55.5 (+), 42.2 (ꢀ), 39.0 (ꢀ), 35.2, 13.9 (+), 12.8
(+); FT IR (KBr, cmꢀ1): 2972, 2934, 1752, 1625, 1505, 1442,
1250, 1177, 1030, 835, 700; HRMS (TOF ES): Found
322.1799, calculated for C21H24NO2 (M+H) 322.1807 (2.5
ppm).
and concentrated. The product was then purified by silica gel
column chromatography eluting with 40:1 CH2Cl2/EtOAc
mixture to afford the titled compound as a colorless solid, mp
o
80.0ꢀ82.4 C, Rf 0.29. Yield 146.1 mg (0.406 mmol, 53%).
1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 2H), 7.60
(d, J = 8.1 Hz, 2H), 7.35 – 7.15 (m, 6H), 3.62 – 3.43 (m, 2H),
3.38 – 3.24 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1
Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 172.8, 142.0, 131.3
(q, J = 32.3 Hz), 130.6 (+, 2C), 129.9, 128.7 (+, 2C), 126.7
(+), 126.1 (+, 2C), 125.7 (q, J = 3.8 Hz, +, 2C), 124.0 (q, J =
272.4 Hz), 122.3, 101.3 (+), 42.2 (ꢀ), 39.1 (ꢀ), 35.8, 13.9 (+),
12.7 (+); 19F NMR (376 MHz, CDCl3) δ ꢀ62.85 (s, 3F); FT
IR (KBr, cmꢀ1): 3082, 2976, 2936, 1626, 1430, 1323, 1277,
1166, 1124, 1064, 846, 712, 699; HRMS (TOF ES): Found
382.1385, calculated for C21H20F3NONa (M+Na) 382.1395
(2.6 ppm).
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N,N-Diethyl-1-phenyl-2-(4-
(trifluoromethyl)phenyl)cycloprop-2-ene-1-carboxamide
(38f): Part I. 1ꢀEthynylꢀ4ꢀ(trifluoromethyl)benzene (35f) (2.0
g, 11.7 mmol, 1.5 equiv.) and rhodium(II) acetate dimer (35.0
mg, 0.157 mmol, 0.02 equiv.) were dissolved in 10 mL of
dichloromethane in a twoꢀneck flask under a nitrogen atmosꢀ
phere at room temperature. Methyl 2ꢀdiazoꢀ2ꢀphenylacetate
(1.38 g, 7.84 mmol, 1.0 equiv.) dissolved in 5 mL dichloroꢀ
methane was then added to the reaction via syringe pump over
18 h. The reaction mixture then was concentrated under reꢀ
duced pressure and the product was coarsely purified by silica
gel Flush column chromatography eluting with a mixture of
hexane and ethyl acetate (3:1). The resulting ester 36f was
directly carried into hydrolysis. Part II: A solution of methyl
1ꢀphenylꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)cyclopropꢀ2ꢀeneꢀ1ꢀ
carboxylate (36f) (375 mg, 1.18 mmol, 1.0 equiv.) in a 1:1
mixture of methanol and tetrahydrofuran (15 mL) was stirred
Copper-Catalyzed Carbomagnesiation
(1S*,2R*)-N,N-Diethyl-2-methyl-1-phenylcyclopropane-
1-carboxamide (15aa), Typical Procedure A: A flame dried
25 mL Schlenk flask was charged with copper iodide (3.0 mg,
15.0 ꢁmol, 5.0 mol%) and freshly distilled anhydrous diꢀ
o
methoxyethane (1.0 mL) under a nitrogen atmosphere at 0 C.
Methylmagnesium bromide (9a) (3.0 M in diethyl ether, 135
ꢁL, 0.405 mmol, 1.35 equiv.) was added dropwise, and the
o
resulting mixture was stirred for five minutes at 0 C. N,Nꢀ
Diethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0
mg, 0.30 mmol, 1.0 equiv.) was then added slowly as a soluꢀ
tion in dry dimethoxyethane (1.0 mL). After five minutes of
stirring at 0 oC, saturated aqueous ammonium chloride (1 mL)
was added dropwise and the reaction was stirred for another
o
o
at 0 C. A 1.5 M aqueous solution of sodium hydroxide (8
five minutes at 0 C. The resulting solution was then diluted
mL) was added dropwise and the mixture was stirred for 18 h.
Organic solvents were then removed under vacuum and the
remaining aqueous solution was added to dichloromethane (15
mL). The mixture was acidified to pH 2 with 1N aqueous HCl.
The organic phase was separated and the aqueous layer was
extracted with dichloromethane (3 x 10 mL). The combined
organic phases were washed with brine, dried with MgSO4,
filtered, and concentrated. The crude carboxylic acid was obꢀ
tained in 65% yield (234 mg, 0.77 mmol) and was immediateꢀ
ly carried to amide coupling without further purification. Part
III. 1ꢀPhenylꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)cyclopropꢀ2ꢀeneꢀ
1ꢀcarboxylic acid (230 mg, 0.760 mmol, 1.0 equiv.) and dimeꢀ
thylformamide (2 drops) were dissolved in freshly distilled
and dried dichloromethane (7 ml) and added to a flame dried
round bottom flask under an inert nitrogen atmosphere. Oxalyl
chloride (100 ꢁL, 143 mg, 1.13 mmol, 1.5 equiv.) was then
added slowly dropwise and stirred at room temperature for 2
hours. The solution was then evaporated under reduced presꢀ
sure to provide a pale yellow solid material. This material was
dissolved in freshly dried dichloromethane (6.0 ml) and slowly
added to a stirred mixture of diethylamine (158.0 ꢁL, 111.1
mg, 1.52 mmol, 2.0 equiv.) and triethylamine (212 ꢁL, 153.8
mg, 1.52 mmol, 2.0 equiv.), and freshly dried dichloromethane
(6.0 mL) under an inert nitrogen atmosphere. The reaction was
then stirred for 18 hours and then partitioned between water
and dichloromethane. The aqueous phase was then acidified
using 1N HCl to a pH of approximately 2. The organic phase
was then extracted with properly acidified water (pH = 2, 3 x
10ml). The combined acidic aqueous layers were then back
extracted once with dichloromethane which was combined
with water and extracted with diethyl ether (3 x 5 mL). Comꢀ
bined organic layers were washed with brine, dried with magꢀ
nesium sulfate, filtered, and evaporated. The product was puriꢀ
fied by column chromatography on Silica gel eluting with
hexane/EtOAc (mixture 3:1). The titled compound was obꢀ
tained as a viscous colorless oil, Rf 0.45. Yield 66.4 mg
(0.287 mmol, 96%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ
7.31 – 7.11 (m, 5H), 3.69 – 3.46 (m, 2H), 3.18 (dq, J = 13.9,
7.0 Hz, 1H), 3.07 (dq, J = 14.0, 7.0 Hz, 1H), 1.96 – 1.81 (m,
1H), 1.40 (dd, J = 6.3, 4.6 Hz, 1H), 1.13 (d, J = 6.3 Hz, 3H),
1.10 (t, J = 7.1 Hz, 3H), 0.85 (dd, J = 8.8, 4.6 Hz, 1H), 0.54 (t,
J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.5, 141.9,
128.7 (+, 2C), 126.2 (+, 3C), 41.4 (ꢀ), 39.2 (ꢀ), 35.5, 23.6 (ꢀ),
18.3 (+), 14.7 (+), 12.7 (+), 12.5 (+); FTIR (KBr, cmꢀ1): 3059,
3001, 2969, 2933, 2872, 1643, 1600, 1494, 1444, 1417, 1381,
1363, 1348, 1317, 1298, 1278, 1236, 1220, 1139, 1103, 1091,
761, 736; HRMS (TOF ES): Found 254.1528, calculated for
C15H21NONa (M+Na) 254.1521 (2.8 ppm).
(1S*,2R*)-N,N,2-Triethyl-1-phenylcyclopropane-1-
carboxamide (15ab), Typical Procedure B: A flame dried
25 mL Schlenk flask was charged with copper iodide (3.0 mg,
15.0 ꢁmol, 5.0 mol%) and freshly distilled anhydrous diꢀ
methoxyethane (1.0 mL) under a nitrogen atmosphere at ꢀ45
oC. Ethylmagnesium bromide (9b) (3.0 M in diethyl ether,
135 ꢁL, 0.405 mmol, 1.35 equiv.) was added dropwise and the
mixture was stirred for five minutes at ꢀ45 oC. N,NꢀDiethylꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0 mg, 0.30
mmol, 1.0 equiv.) was then added slowly as a solution in dry
dimethoxyethane (1.0 mL). The reaction was then stirred for
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The Journal of Organic Chemistry
60 minutes at ꢀ45 oC. Water was then added very slowly
Page 14 of 29
168.6, 141.3, 137.2, 128.8 (+, 2C), 128.2 (+, 2C), 127.4 (+,
1
2
3
4
5
6
7
8
dropwise. After ten minutes of stirring, saturated aqueous
ammonium chloride (1 mL) was added and the reaction was
allowed to warm to room temperature. The resulting solution
was then diluted with water and extracted with diethyl ether (3
x 5 mL). Combined organic layers were washed with brine,
dried with magnesium sulfate, filtered, and evaporated. The
product was purified by column chromatography on Silica gel
eluting with hexane/EtOAc (mixture 3:1). The titled comꢀ
pound was obtained as a viscous colorless oil, Rf 0.42. Yield
61.1 mg (0.249 mmol, 83%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.36 – 7.13 (m, 5H), 3.67 – 3.47 (m, 2H), 3.17 (dq, J
= 13.9, 7.0 Hz, 1H), 3.05 (dq, J = 14.1, 7.0 Hz, 1H), 1.83 –
1.77 (m, 1H), 1.76 – 1.68 (m, 1H), 1.40 (dd, J = 6.3, 4.6 Hz,
1H), 1.10 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H), 0.99 –
0.93 (m, 1H), 0.84 (dd, J = 8.8, 4.5 Hz, 1H), 0.53 (t, J = 7.1
Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.6, 142.0, 128.7
(+, 2C), 126.3 (+, 2C), 126.2 (+), 41.6 (ꢀ), 39.3 (ꢀ), 35.7, 26.1
(+), 23.1 (ꢀ), 22.2 (ꢀ), 13.8 (+), 12.7 (+), 12.5 (+); FTIR (KBr,
cmꢀ1): 3059, 3024, 2966, 2931, 2872, 1643, 1600, 1494, 1444,
1417, 1381, 1361, 1346, 1315, 1298, 1276, 1220, 1139, 1099,
1068, 771, 754; HRMS (TOF ES): Found 268.1684, calculatꢀ
ed for C16H23NONa (M+Na) 268.1677 (2.6 ppm).
2C), 126.6 (+), 126.5 (+), 126.1 (+, 2C), 41.0 (ꢀ), 40.4, 38.7 (ꢀ
), 29.3 (+), 22.5 (ꢀ), 12.1 (+), 11.8 (+); FTIR (KBr, cmꢀ1):
3294, 3242, 3201, 3086, 3061, 3026, 3009, 2976, 2935, 2874,
1633, 1606, 1589, 1494, 1444, 1429, 1381, 1361, 1317, 1274,
1236, 1220, 1138, 771, 754, 732; HRMS (TOF ES): Found
316.1678, calculated for C20H23NONa (M+Na) 316.1677 (0.3
ppm).
(1S*,2S*)-N,N-Diethyl-1-phenyl-2-vinylcyclopropane-1-
carboxamide (15ae): This compound was obtained via Typiꢀ
cal procedure A employing vinylmagnesium bromide (9e) (1.0
M in THF, 405 ꢁL, 0.405 mmol, 1.35 equiv.) and N,Nꢀdiethylꢀ
1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
matography on Silica gel eluting with hexane/EtOAc (mixture
3:1). The titled compound was obtained as a viscous colorless
oil, Rf 0.39. Yield 70.8 mg (0.291 mmol, 97%), dr >99:1. 1H
NMR (500 MHz, CDCl3) δ 7.34 – 7.17 (m, 5H), 5.46 – 5.35
(m, 1H), 5.28 (dd, J = 17.0, 1.7 Hz, 1H), 5.05 (dd, J = 10.1,
1.7 Hz, 1H), 3.57 – 3.49 (m, 1H), 3.49 – 3.40 (m, 1H), 3.17
(dq, J = 14.0, 7.0 Hz, 1H), 3.01 (dq, J = 14.2, 7.0 Hz, 1H),
2.60 – 2.51 (m, 1H), 1.80 (dd, J = 6.2, 4.9 Hz, 1H), 1.13 –
1.05 (m, 4H), 0.55 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 169.7, 140.9, 136.7 (+), 128.8 (+, 2C), 126.6 (+),
126.0 (+, 2C), 115.8 (ꢀ), 41.3 (ꢀ), 39.3 (ꢀ), 37.2, 28.3 (+), 23.4
(ꢀ), 12.7 (+), 12.4 (+); FTIR (KBr, cmꢀ1): 3082, 3059, 3003,
2974, 2935, 2874, 1643, 1624, 1494, 1460, 1427, 1381, 1363,
1346, 1315, 1294, 1276, 1220, 1136, 1101, 1078, 1068, 1030,
989, 949, 902, 786, 759; HRMS (TOF ES): Found 244.1704,
calculated for C16H22NO (M+H) 244.1701 (1.2 ppm).
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(1S*,2R*)-N,N-Diethyl-2-isobutyl-1-
phenylcyclopropane-1-carboxamide (15ac): This compound
was obtained via Typical procedure B employing isobutylꢀ
magnesium bromide (9c) (1.0 M in THF, 405 ꢁL, 0.405 mmol,
1.35 equiv.) and N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxamide (11a) (65.0 mg, 0.30 mmol, 1.0 equiv.). The
product was purified by column chromatography on Silica gel
eluting with hexane/EtOAc (mixture 6:1). The titled comꢀ
pound was obtained as a viscous colorless oil, Rf 0.26. Yield
74.2 mg (0.271 mmol, 90%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.35 – 7.11 (m, 5H), 3.63 – 3.49 (m, 2H), 3.18 (dq, J
= 13.9, 7.0 Hz, 1H), 3.04 (dq, J = 14.1, 7.0 Hz, 1H), 1.89 –
1.81 (m, 1H), 1.79 – 1.69 (m, 1H), 1.63 – 1.53 (m, 1H), 1.45
(dd, J = 6.4, 4.5 Hz, 1H), 1.10 (t, J = 7.1 Hz, 3H), 0.97 (d, J =
5.5 Hz, 3H), 0.96 (d, J = 6.1 Hz, 3H), 0.88 (dd, J = 8.8, 4.5
Hz, 1H), 0.84 – 0.77 (m, 1H), 0.52 (t, J = 7.1 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 170.6, 142.1, 128.7 (+, 2C), 126.4
(+, 2C), 126.3 (+), 41.6 (ꢀ), 39.3 (ꢀ), 38.5 (ꢀ), 34.7, 28.6 (+),
23.0 (ꢀ), 22.9 (+), 22.7 (+), 22.6 (+), 12.6 (+), 12.5 (+); FTIR
(KBr, cmꢀ1): 3059, 2955, 2933, 2870, 1643, 1633, 1600, 1494,
1442, 1427, 1381, 1365, 1346, 1317, 1294, 1276, 1242, 1220,
1139, 1101, 1068, 1031, 759, 742; HRMS (TOF ES): Found
296.1978, calculated for C18H27NONa (M+Na) 296.1990 (4.1
ppm).
(1S*,2R*)-2-Allyl-N,N-diethyl-1-phenylcyclopropane-1-
carboxamide (15af): This compound was obtained via Typiꢀ
cal procedure A employing allylmagnesium bromide (9f) (1.0
M in diethyl ether, 405 ꢁL, 0.405 mmol, 1.35 equiv.) and N,Nꢀ
diethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0
mg, 0.30 mmol, 1.0 equiv.). The product was purified by colꢀ
umn chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a colorꢀ
less oil, Rf 0.39. Yield 72.2 mg (0.280 mmol, 94%), dr >99:1.
1H NMR (500 MHz, CDCl3) δ 7.33 – 7.24 (m, 2H), 7.24 –
7.13 (m, 3H), 5.93 (dddd, J = 17.1, 10.2, 6.9, 5.9 Hz, 1H),
5.13 (dd, J = 17.2, 1.7 Hz, 1H), 5.03 (dd, J = 10.3, 1.7 Hz,
1H), 3.69 – 3.49 (m, 2H), 3.18 (dq, J = 14.0, 7.1 Hz, 1H), 3.04
(dq, J = 14.1, 7.0 Hz, 1H), 2.46 – 2.32 (m, 1H), 1.96 – 1.84
(m, 1H), 1.84 – 1.72 (m, 1H), 1.48 (dd, J = 6.3, 4.7 Hz, 1H),
1.11 (t, J = 7.1 Hz, 3H), 0.92 (dd, J = 8.8, 4.7 Hz, 1H), 0.52 (t,
J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.3, 141.7,
137.2 (+), 128.7 (+, 2C), 126.4 (+, 2C), 126.4 (+), 115.4 (ꢀ),
41.8 (ꢀ), 39.4 (ꢀ), 35.4, 34.0 (ꢀ), 23.5 (+), 22.1 (ꢀ), 12.6 (+),
12.6 (+); FTIR (KBr, cmꢀ1): 3076, 3063, 2976, 2933, 2874,
1643, 1633, 1494, 1442, 1427, 1381, 1363, 1346, 1317, 1296,
1278, 1238, 1220, 1139, 1101, 1078, 1031, 995, 912, 761;
HRMS (TOF ES): Found 280.1683, calculated for
C17H23NONa (M+Na) 280.1677 (2.1 ppm).
(1S*,2S*)-N,N-Diethyl-1,2-diphenylcyclopropane-1-
carboxamide (15ad): This compound was obtained via Typiꢀ
cal procedure A employing phenylmagnesium bromide (9d)
(3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.) and
N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(11a)
(65.0 mg, 0.30 mmol, 1.0 equiv.). The product was purified by
column chromatography on Silica gel eluting with hexꢀ
ane/EtOAc (mixture 6:1). The titled compound was obtained
as a viscous colorless oil, Rf 0.32. Yield 82.2 mg (0.280 mmol,
93%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.14
(m, 10H), 3.41 (dq, J = 14.1, 7.1 Hz, 1H), 3.31 (dq, J = 14.2,
7.2 Hz, 1H), 3.10 (dd, J = 9.1, 6.9 Hz, 1H), 2.81 (dq, J = 14.0,
7.0 Hz, 1H), 2.52 (dq, J = 14.1, 7.0 Hz, 1H), 2.33 (dd, J = 6.9,
5.4 Hz, 1H), 1.27 (dd, J = 9.1, 5.4 Hz, 1H), 0.66 (t, J = 7.1 Hz,
3H), 0.26 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
(1S*,2R*)-N,N-Diethyl-1-phenyl-2-
((trimethylsilyl)methyl)cyclopropane-1-carboxamide
(15ag): This compound was obtained via Typical procedure A
employing (trimethylsilyl)methylmagnesium chloride (9g)
(1.3 M in THF, 300 ꢁL, 0.40 mmol, 1.30 equiv.), (and N,Nꢀ
diethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0
mg, 0.30 mmol, 1.0 equiv.). The product was purified by colꢀ
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The Journal of Organic Chemistry
1H), 1.43 (d, J = 6.8 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 1.39
umn chromatography on Silica gel eluting with hexane/EtOAc
1
2
3
4
5
6
7
8
(mixture 3:1). The titled compound was obtained as a colorꢀ
less oil, Rf 0.34. Yield 76.6 mg (0.252 mmol, 84%), dr >99:1.
1H NMR (500 MHz, CDCl3) δ 7.29 – 7.26 (m, 1H), 7.25 (s,
1H), 7.21 – 7.14 (m, 3H), 3.65 – 3.48 (m, 2H), 3.24 (dq, J =
13.9, 7.0 Hz, 1H), 3.08 (dq, J = 14.1, 7.0 Hz, 1H), 1.82 (dddd,
J = 12.3, 8.9, 6.3, 2.6 Hz, 1H), 1.38 (dd, J = 6.4, 4.6 Hz, 1H),
1.12 (t, J = 7.1 Hz, 3H), 0.93 (dd, J = 14.3, 2.6 Hz, 1H), 0.90
(dd, J = 8.8, 4.7 Hz, 1H), 0.56 (t, J = 7.1 Hz, 3H), 0.15 (dd, J
= 14.3, 12.3 Hz, 1H), 0.08 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 172.1 , 143.5 , 130.0 (+, 2C) , 127.6 (+, 2C) , 127.5
(+) , 42.8 (ꢀ) , 40.6 (ꢀ) , 36.8 , 25.4 (ꢀ) , 21.5 (+) , 18.0 (ꢀ) ,
14.1 (+) , 14.0 (+) , 0.0 (+, 3C); FT IR (KBr, cmꢀ1): 2953,
2874, 1634, 1496, 1457, 1442, 1425, 1379, 1273, 1247, 861,
844, 785, 699; HRMS (TOF ES): Found 326.1926, calculated
for C18H29NOSiNa (M+Na) 326.1916 (3.1 ppm).
(dd, J = 6.25, 4.57 Hz, 1H), 1.20 (d, J = 6.3 Hz, 3H), 1.08 (d, J
= 6.7 Hz, 3H), 0.77 (dd, J = 8.9, 4.5 Hz, 1H), 0.36 (d, J = 6.6
Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.1, 142.2, 128.6
(+, 2C), 126.6 (+, 2C), 126.2 (+), 48.9 (+), 45.9 (+), 37.2, 22.8
(ꢀ), 21.8 (+), 21.1 (+), 19.7 (+), 19.2 (+), 18.0 (+), 15.1 (+);
FTIR (KBr, cmꢀ1): 3059, 2999, 2962, 2931, 2872, 1633, 1600,
1494, 1435, 1369, 1336, 1238, 1211, 1157, 1134, 1091, 1039,
734; HRMS (TOF ES): Found 282.1844, calculated for
C17H25NONa (M+Na) 282.1834 (3.5 ppm).
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15
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17
18
19
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(1S*,2S*)-N,N-Diisopropyl-1,2-diphenylcyclopropane-1-
carboxamide (15bd): This compound was obtained via Typꢀ
ical procedure A employing phenylmagnesium bromide (9d)
(3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.) and
N,Nꢀdiisopropylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(11b) (73.0 mg, 0.30 mmol, 1.0 equiv.). The product was puriꢀ
fied by column chromatography on Silica gel eluting with
hexane/EtOAc (mixture 6:1). The titled compound was obꢀ
(1S*,2S*)-N,N-diethyl-1-phenyl-2-
(phenylethynyl)cyclopropane-1-carboxamide (15ah): Flame
dried Schlenk flask was charged with phenylacetylene (53.0
ꢁL, 0.480 mmol, 1.60 equiv.) and dry dimethoxyethane (1
mL) under a nitrogen atmosphere. Methylmagnesium broꢀ
mide (9a) (3.0 M in diethyl ether, 150 ꢁL, 0.450 mmol, 1.50
equiv.) was added dropwise, and the reaction was then stirred
o
tained as a colorless solid, mp 132.8ꢀ135.5 C, Rf 0.42. Yield
87.8 mg (0.273 mmol, 91%), dr 20:1. 1H NMR (500 MHz,
CDCl3) δ 7.50 – 7.15 (m, 10H), 4.03 – 3.88 (m, 1H), 3.11 (dd,
J = 9.3, 6.9 Hz, 1H), 3.01 – 2.89 (m, 1H), 2.24 (dd, J = 6.9,
5.3 Hz, 1H), 1.34 (d, J = 6.7 Hz, 3H), 1.23 (dd, J = 9.2, 5.3
Hz, 1H), 1.18 (d, J = 6.8 Hz, 3H), 0.21 (d, J = 6.6 Hz, 3H),
0.06 (d, J = 6.6 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
168.4, 141.3, 138.2, 128.7 (+, 2C), 128.4 (+, 2C), 127.4 (+,
2C), 126.7 (+, 2C), 126.7 (+), 126.5 (+), 48.8 (+), 45.9 (+),
42.2, 28.5 (+), 23.2 (ꢀ), 20.3 (+), 20.2 (+), 19.5 (+), 19.1 (+);
FTIR (KBr, cmꢀ1): 3059, 3028, 3007, 2960, 2931, 1620, 1496,
1469, 1444, 1369, 1342, 1209, 1157, 1134, 1122, 1078, 1057,
1037, 1022, 800, 773, 758, 734, 704; HRMS (TOF ES):
Found 322.2172, calculated for C22H28NO (M+H) 322.2171
(0.3 ppm).
o
at 55 C for one hour. The solution was then cooled to room
temperature and cannulated into another Schlenk flask conꢀ
taining copper iodide (3.0 mg, 15.0 ꢁmol, 5 mol%) and dry
dimethoxyethane (1 mL). After 5 minutes of stirring, N,Nꢀ
diethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0
mg, 0.30 mmol, 1.0 equiv.) as a solution in dry dimethoxyeꢀ
thane (1 mL) was added dropwise and the reaction was stirred
for 60 minutes at 0 oC. Saturated aqueous ammonium chloride
(1 mL) was then added dropwise. The resulting solution was
diluted with water and extracted with diethyl ether (3 x 5 mL).
The combined organic layers were washed with brine, dried,
filtered, and evaporated. The product was purified by column
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a viscous
yellowish oil, Rf 0.35. Yield 9.4 mg (0.03 mmol, 10%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.15 (m, 10H),
3.66 – 3.57 (m, 1H), 3.57 – 3.49 (m, 1H), 3.20 – 3.04 (m, 2H),
2.62 (dd, J = 9.0, 6.2 Hz, 1H), 2.03 (dd, J = 6.2, 4.6 Hz, 1H),
1.13 (dd, J = 9.0, 4.5 Hz, 1H), 0.99 (t, J = 7.1 Hz, 3H), 0.56 (t,
J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 168.8, 139.6,
131.7 (+, 2C), 128.9 (+, 2C), 128.3 (+, 2C), 128.0 (+), 127.1
(+), 126.3 (+, 2C), 123.4, 88.0, 79.6, 41.7 (+), 39.6 (+), 38.3,
25.0 (+), 13.8 (ꢀ), 12.8 (ꢀ), 12.6 (ꢀ); FTIR (KBr, cmꢀ1): 3059,
2968, 2926, 2852, 1645, 1635, 1558, 1539, 1506, 1456, 1429,
1219, 1134, 1068, 1026, 945, 910, 842, 758; HRMS (TOF
ES): Found 340.1689, calculated for C22H23NONa (M+Na)
340.1677 (3.5 ppm).
(1S*,2S*)-N,N-diisopropyl-1-phenyl-2-
vinylcyclopropane-1-carboxamide (15be): This compound
was obtained via Typical procedure A employing vinylꢀ
magnesium bromide (9e) (1.0 M in THF, 405 ꢁL, 0.405 mmol,
1.35 equiv.) and N,Nꢀdiisopropylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxamide (11b) (73.0 mg, 0.30 mmol, 1.0 equiv.). The
product was purified by column chromatography on Silica gel
eluting with hexane/EtOAc (mixture 3:1). The titled comꢀ
pound was obtained as a viscous colorless oil, Rf 0.55. Yield
71.8 mg (0.265 mmol, 88%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.43 – 7.11 (m, 5H), 5.54 – 5.38 (m, 1H), 5.31 (dd, J
= 17.0, 1.7 Hz, 1H), 5.08 (dd, J = 10.1, 1.7 Hz, 1H), 4.16
(hept, J = 6.6 Hz, 1H), 3.20 (hept, J = 6.8 Hz, 1H), 2.74 – 2.44
(m, 1H), 1.78 (dd, J = 6.1, 4.8 Hz, 1H), 1.41 (d, J = 6.8 Hz,
3H), 1.41 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H), 1.02 –
0.98 (m, 1H), 0.35 (d, J = 6.6 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 169.3, 140.9, 137.3 (+), 128.7 (+, 2C), 126.6 (+),
126.4 (+, 2C), 115.5 (ꢀ), 49.0 (+), 45.9 (+), 38.8, 27.7 (+), 23.0
(ꢀ), 21.8 (+), 20.9 (+), 19.6 (+), 19.2 (+); FTIR (KBr, cmꢀ1):
3082, 3061, 3001, 2964, 2931, 2874, 1633, 1600, 1494, 1471,
1437, 1369, 1338, 1215, 1157, 1132, 1037, 989, 902, 761,
742, 700; HRMS (TOF ES): Found 272.2018, calculated for
C18H26NO (M+H) 272.2014 (1.5 ppm).
(1S*,2R*)-N,N-diisopropyl-2-methyl-1-
phenylcyclopropane-1-carboxamide (15ba): This compoꢀ
und was obtained via Typical procedure A employing methylꢀ
magnesium bromide (9a) (3.0 M in diethyl ether, 135 ꢁL,
0.405 mmol, 1.35 equiv.) and N,Nꢀdiisopropylꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11b) (73.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
matography on Silica gel eluting with hexane/EtOAc (mixture
6:1). The titled compound was obtained as a viscous colorless
oil, Rf 0.35. Yield 73.2 mg (0.282 mmol, 94%), dr: >99:1. 1H
NMR (500 MHz, CDCl3) δ 7.31 – 7.13 (m, 5H), 4.25 (hept, J
= 6.6 Hz, 1H), 3.22 (hept, J = 6.8 Hz, 1H), 2.00 – 1.84 (m,
(1S*,2R*)-N,N-Dibenzyl-2-methyl-1-
phenylcyclopropane-1-carboxamide (15ca): This compoꢀ
und was obtained via Typical procedure A employing
methylmagnesium bromide (9a) (135 ꢁL (3.0 M in diethyl
ether), 0.405 mmol, 1.35 equiv.) and N,Nꢀdibenzylꢀ1ꢀ
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Page 16 of 29
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (102 mg, 0.30 mmol, 1361, 1315, 1267, 1190, 1078, 1030, 1010, 976, 947, 906,
1
2
3
4
5
6
7
8
1.0 equiv.). The product was purified by column chromatogꢀ
raphy on Silica gel eluting with hexane/EtOAc (mixture 6:1).
The titled compound was obtained as a colorless solid, mp
113.7ꢀ115.1 oC, Rf 0.26. Yield 101 mg (0.285 mmol, 95%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.35 – 7.10 (m, 13H),
6.70 – 6.54 (m, 2H), 4.91 (d, J = 14.4 Hz, 1H), 4.80 (d, J =
15.6 Hz, 1H), 4.24 (d, J = 15.6 Hz, 1H), 4.01 (d, J = 14.4 Hz,
1H), 1.96 – 1.81 (m, 1H), 1.44 (dd, J = 6.3, 4.6 Hz, 1H), 1.25
(d, J = 6.3 Hz, 3H), 1.02 (dd, J = 8.8, 4.6 Hz, 1H); 13C NMR
(126 MHz, CDCl3) δ 171.9, 141.4, 137.4, 136.0, 129.0 (+,
2C), 128.8 (+, 2C), 128.5 (+, 2C), 128.4 (+, 2C), 127.6 (+,
2C), 127.4 (+), 127.4 (+), 127.2 (+, 2C), 126.6 (+), 49.9 (ꢀ),
47.1 (ꢀ), 35.6, 22.5 (ꢀ), 19.3 (+), 15.6 (+); FTIR (KBr, cmꢀ1):
3061, 3028, 3003, 2956, 2928, 2868, 2359, 2341, 1633, 1600,
1494, 1450, 1417, 1361, 1317, 1296, 1193, 1078, 1028, 989,
752, 732; HRMS (TOF ES): Found 378.1842, calculated for
C25H25NONa (M+Na) 378.1834 (2.1 ppm).
750, 736, 700; HRMS (TOF ES): Found 368.2026, calculated
for C26H26NO (M+H) 368.2014 (3.3 ppm).
((1S*,2R*)-2-methyl-1-phenylcyclopropyl)(pyrrolidin-1-
yl)methanone (15da): This compound was obtained via Typiꢀ
cal procedure A employing methylmagnesium bromide (9a)
(3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.) and
(1ꢀphenylcyclopropꢀ2ꢀenꢀ1ꢀyl)(pyrrolidinꢀ1ꢀyl)methanone
(11d) (64.0 mg, 0.30 mmol, 1.0 equiv.). The product was puriꢀ
fied by column chromatography on Silica gel eluting with
hexane/EtOAc (mixture 3:1). The titled compound was obꢀ
tained as a viscous colorless oil, Rf 0.16. Yield (62.8 mg,
0.274 mmol, 91%), dr >99:1; 1H NMR (500 MHz, CDCl3) δ
7.30 – 7.14 (m, 5H), 3.57 – 3.48 (m, 2H), 3.41 – 3.32 (m, 1H),
2.91 – 2.79 (m, 1H), 1.91 – 1.79 (m, 2H), 1.79 – 1.64 (m, 3H),
1.44 (dd, J = 6.3, 4.6 Hz, 1H), 1.14 (d, J = 6.2 Hz, 3H), 0.89
(dd, J = 8.7, 4.6 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
169.6, 141.3, 128.7 (+, 2C), 126.2 (+, 2C), 126.2 (+), 47.1 (ꢀ),
46.3 (ꢀ), 36.6, 26.4 (ꢀ), 24.2 (ꢀ), 23.4 (ꢀ), 18.7 (+), 14.8 (+);
FTIR (KBr, cmꢀ1): 3057, 2999, 2996, 2953, 2929, 2874, 1633,
1600, 1579, 1494, 1717, 1367, 1342, 1192, 1168, 1095, 1033,
912, 756, 734, 725, 700; HRMS (TOF ES): Found 252.1376,
calculated for C15H19NONa (M+Na) 252.1364 (4.8 ppm).
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10
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12
13
14
15
16
17
18
19
20
21
22
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27
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(1S*,2S*)-N,N-Dibenzyl-1,2-diphenylcyclopropane-1-
carboxamide (15cd): This compound was obtained via Typiꢀ
cal procedure A employing phenylmagnesium bromide (9d)
(3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.) and
N,Nꢀdibenzylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11c)
(102 mg, 0.30 mmol, 1.0 equiv.). The product was purified by
column chromatography on Silica gel eluting with hexꢀ
ane/EtOAc (mixture 6:1). The titled compound was obtained
as a viscous yellowish oil, Rf 0.30. Yield 117 mg (0.280
mmol, 93%), dr 13:1. 1H NMR (500 MHz, CDCl3) δ 7.50 –
7.41 (m, 2H), 7.36 – 6.93 (m, 14H), 6.69 – 6.56 (m, 2H), 6.19
– 6.05 (m, 2H), 4.58 (d, J = 14.7 Hz, 1H), 4.57 (d, J = 15.36
Hz, 1H), 3.88 (d, J = 14.8 Hz, 1H), 3.76 (d, J = 15.4 Hz, 1H),
3.20 (dd, J = 9.2, 7.0 Hz, 1H), 2.46 (dd, J = 7.0, 5.3 Hz, 1H),
1.34 (dd, J = 9.2, 5.3 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
170.2, 141.1, 137.1, 136.5, 135.4, 129.0 (+, 2C), 128.8 (+,
2C), 128.5 (+, 2C), 128.2 (+, 2C), 128.2 (+, 2C), 127.8 (+,
2C), 127.8 (+, 2C), 127.5 (+, 2C), 127.2 (+), 127.1 (+), 126.9
(+), 126.8 (+), 50.0 (ꢀ), 46.9 (ꢀ), 40.9, 29.0 (+), 21.3 (ꢀ); FTIR
(KBr, cmꢀ1): 3086, 3061, 3028, 3009, 1643, 1604, 1591, 1583,
1494, 1454, 1417, 1361, 1313, 1294, 1267, 1209, 1182, 1078,
1030, 1012, 945, 779, 731; HRMS (TOF ES): Found
440.1988, calculated for C30H27NONa (M+Na) 440.1990 (0.5
ppm).
((1S*,2S*)-1,2-Diphenylcyclopropyl)(pyrrolidin-1-yl)-
methanone (15dd): This compound was obtained via Typical
procedure A employing phenylmagnesium bromide (9d) (3.0
M in diethyl ether, 135 ꢁL 0.405 mmol, 1.35 equiv.) and (1ꢀ
phenylcyclopropꢀ2ꢀenꢀ1ꢀyl)(pyrrolidinꢀ1ꢀyl)methanone (11d)
(64.0 mg, 0.30 mmol, 1.0 equiv.). The product was purified by
column chromatography on Silica gel eluting with hexꢀ
ane/EtOAc (mixture 3:1). The titled compound was obtained
o
as a colorless solid, mp 111.1ꢀ112.7 C, Rf 0.16. Yield 76.2
mg (0.262 mmol, 87%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.40 – 7.16 (m, 10H), 3.38 – 3.24 (m, 1H), 3.10 –
2.93 (m, 3H), 2.71 – 2.57 (m, 1H), 2.33 (dd, J = 6.9, 5.5 Hz,
1H), 1.57 – 1.31 (m, 3H), 1.35 (dd, J = 9.1, 5.6 Hz, 1H), 0.96
– 0.75 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 167.7, 140.4,
137.5, 128.8 (+, 2C), 128.2 (+, 2C), 127.0 (+, 2C), 126.6 (+),
126.5 (+), 126.2 (+, 2C), 46.5 (ꢀ), 45.9 (ꢀ), 41.6, 29.9 (+), 25.6
(ꢀ), 23.8 (ꢀ), 22.7 (ꢀ); FTIR (KBr, cmꢀ1): 3057, 3028, 2970,
2874, 1626, 1579, 1496, 1448, 1427, 1340, 1190, 1168, 1122,
1078, 1031, 914, 873, 775, 763, 732; HRMS (TOF ES):
Found 314.1523, calculated for C20H21NONa (M+Na)
314.1521 (0.6 ppm).
(1S*,2S*)-N,N-Dibenzyl-1-phenyl-2-vinylcyclopropane-
1-carboxamide (15ce): This compound was obtained via Typꢀ
ical procedure A employing vinylmagnesium bromide (9e)
(1.0 M in THF, 405 ꢁL, 0.405 mmol, 1.35 equiv.) and N,Nꢀ
dibenzylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11c) (102
mg, 0.30 mmol, 1.0 equiv.). The product was purified by colꢀ
umn chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a viscous
colorless oil, Rf 0.52. Yield 92.4 mg (0.251 mmol, 84%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.46 – 7.02 (m, 13H),
6.71 – 6.44 (m, 2H), 5.64 – 5.47 (m, 1H), 5.30 (d, J = 17.0 Hz,
1H), 5.03 (d, J = 10.2 Hz, 1H), 4.87 (d, J = 14.5 Hz, 1H), 4.72
(d, J = 15.6 Hz, 1H), 4.15 (d, J = 15.6 Hz, 1H), 3.96 (d, J =
14.5 Hz, 1H), 2.64 – 2.42 (m, 1H), 1.85 (dd, J = 6.2, 4.9 Hz,
1H), 1.22 (dd, J = 8.7, 4.9 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 171.1, 140.3, 137.2, 136.7 (+), 135.8, 129.0 (+, 2C),
129.0 (+, 2C), 128.4 (+, 2C), 128.4 (+, 2C), 127.9 (+, 2C),
127.4 (+), 127.4 (+), 127.1 (+, 2C), 127.0 (+), 116.3 (ꢀ), 50.0
(ꢀ), 47.1 (ꢀ), 37.4, 28.5 (+), 22.2 (ꢀ); FTIR (KBr, cmꢀ1): 3084,
3061, 3028, 3005, 2822, 1643, 1633, 1600, 1494, 1448, 1417,
((1S*,2S*)-1-Phenyl-2-vinylcyclopropyl)(pyrrolidin-1-
yl)methanone (15de): This compound was obtained via Typiꢀ
cal procedure A employing vinylmagnesium bromide (9e) (1.0
M in THF, 405 ꢁL, 0.405 mmol, 1.35 equiv.) and (1ꢀphenylꢀ
cyclopropꢀ2ꢀenꢀ1ꢀyl)(pyrrolidinꢀ1ꢀyl)methanone (11d) (64.0
mg, 0.30 mmol, 1.0 equiv.). The product was purified by colꢀ
umn chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a viscous
colorless oil, Rf 0.16. Yield 59.2 mg (0.245 mmol, 82%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.33 – 7.27 (m, 2H),
7.23 – 7.17 (m, 3H), 5.51 – 5.35 (m, 1H), 5.30 (dd, J = 17.0,
1.8 Hz, 1H), 5.06 (dd, J = 10.0, 1.8 Hz, 1H), 3.61 – 3.43 (m,
2H), 3.45 – 3.31 (m, 1H), 2.90 – 2.71 (m, 1H), 2.55 – 2.39 (m,
1H), 1.86 – 1.77 (m, 1H), 1.83 (dd, J = 6.2, 5.0 Hz, 1H), 1.77
– 1.59 (m, 3H), 1.12 (dd, J = 8.7, 4.9 Hz, 1H); 13C NMR (126
MHz, CDCl3) δ 168.9, 140.1, 136.9 (+), 128.8 (+, 2C), 126.5
(+), 126.1 (+, 2C), 115.9 (ꢀ), 46.7 (ꢀ), 46.4 (ꢀ), 38.4, 28.6 (+),
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The Journal of Organic Chemistry
26.3 (ꢀ), 24.2 (ꢀ), 23.3 (ꢀ); FTIR (KBr, cmꢀ1): 3080, 3057,
1H), 3.52 – 3.43 (m, 1H), 3.34 – 3.25 (m, 1H), 3.25 – 3.18 (m,
1
2
3
4
5
6
7
8
3022, 3001, 2970, 2874, 1633, 1600, 1579, 1494, 1423, 1340,
1190, 1168, 1114, 1031, 993, 941, 910, 758, 727, 700; HRMS
(TOF ES): Found 264.1377, calculated for C16H19NONa
(M+Na) 264.1364 (4.9 ppm).
1H), 2.59 – 2.48 (m, 1H), 1.78 (dd, J = 6.2, 5.0 Hz, 1H), 1.55
– 1.44 (m, 4H), 1.32 – 1.23 (m, 1H), 1.15 (dd, J = 8.7, 5.0 Hz,
1H), 1.06 – 0.94 (m, 1H); 13C NMR (126 MHz, CDCl3) δ
168.9, 140.9, 137.1 (+), 128.8 (+, 2C), 126.5 (+), 125.5 (+,
2C), 115.8 (ꢀ), 46.7 (ꢀ), 43.3 (ꢀ), 37.1, 29.4 (+), 25.8 (ꢀ), 25.7 (ꢀ
), 24.5 (ꢀ), 23.8 (ꢀ); FTIR (KBr, cmꢀ1): 3080, 3059, 3003,
2935, 2854, 1643, 1626, 1496, 1435, 1369, 1352, 1271, 1257,
1207, 1136, 1126, 1103, 1031, 1010, 983, 952, 902, 852, 758,
742; HRMS (TOF ES): Found 278.1529, calculated for
C17H21NONa (M+Na) 278.1521 (2.9 ppm).
((1S*,2R*)-2-methyl-1-phenylcyclopropyl)(piperidin-1-
yl)methanone (15ea): This compound was obtained via Typꢀ
ical procedure A employing methylmagnesium bromide (9a)
(3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.) and
(1ꢀphenylcyclopropꢀ2ꢀenꢀ1ꢀyl)(piperidinꢀ1ꢀyl)methanone
(11e) (68.0 mg, 0.30 mmol, 1.0 equiv.). The product was puriꢀ
fied by column chromatography on Silica gel eluting with
hexane/EtOAc (mixture 6:1). The titled compound was obꢀ
tained as a viscous colorless oil, Rf 0.16. Yield 65.6 mg
(0.270 mmol, 90%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ
7.33 – 7.11 (m, 5H), 3.82 – 3.71 (m, 1H), 3.49 – 3.35 (m, 2H),
3.31 – 3.20 (m, 1H), 1.92 – 1.81 (m, 1H), 1.59 – 1.44 (m, 4H),
1.38 (dd, J = 6.3, 4.7 Hz, 1H), 1.31 – 1.20 (m, 1H), 1.17 (d, J
= 6.3 Hz, 3H), 1.09 – 0.96 (m, 1H), 0.91 (dd, J = 8.8, 4.7 Hz,
1H); 13C NMR (126 MHz, CDCl3) δ 169.6, 141.9, 128.7 (+,
2C), 126.1 (+), 125.7 (+, 2C), 46.7 (ꢀ), 43.2 (ꢀ), 35.3, 25.8 (ꢀ),
25.7 (ꢀ), 24.6 (ꢀ), 24.0 (ꢀ), 19.4 (+), 15.3 (+); FTIR (KBr, cmꢀ
1): 3059, 3001, 2935, 2854, 1633, 1600, 1496, 1465, 1433,
1294, 1271, 1259, 1211, 1138, 1128, 1022, 1003, 852, 754,
732, 700; HRMS (TOF ES): Found 266.1520, calculated for
C16H21NONa (M+Na) 266.1521 (0.4 ppm).
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12
13
14
15
16
17
18
19
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25
26
27
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((1S*,2R*)-2-Methyl-1-phenylcyclopropyl)(morpholino)-
methanone (15fa): This compound was obtained via Typical
procedure A employing methylmagnesium bromide (9a) (3.0
M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.) and
morpholino(1ꢀphenylcyclopropꢀ2ꢀenꢀ1ꢀyl)methanone
(11f)
(69.0 mg, 0.30 mmol, 1.0 equiv.). The product was purified by
column chromatography on Silica gel eluting with hexꢀ
ane/EtOAc (mixture 3:1). The titled compound was obtained
as a viscous colorless oil, Rf 0.19. Yield 67.6 mg (0.276
mmol, 92%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ 7.34 –
7.11 (m, 5H), 3.74 – 3.66 (m, 2H), 3.66 – 3.59 (m, 2H), 3.45 –
3.31 (m, 3H), 3.27 – 3.19 (m, 1H), 1.95 – 1.81 (m, 1H), 1.40
(dd, J = 6.4, 4.7 Hz, 1H), 1.19 (d, J = 6.2 Hz, 3H), 0.95 (dd, J
= 8.8, 4.7 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 169.9,
141.4, 128.9 (+, 2C), 126.4 (+), 125.5 (+, 2C), 66.9 (ꢀ), 66.6 (ꢀ
), 46.3 (ꢀ), 42.7 (ꢀ), 35.0, 23.9 (ꢀ), 19.3 (+), 15.3 (+); FTIR
(KBr, cmꢀ1): 3062, 2999, 2960, 2920, 2899, 2854, 1639, 1496,
1456, 1427, 1390, 1359, 1301, 1273, 1209, 1114, 1095, 1068,
1030, 1008, 945, 912, 848, 756, 732, 700; HRMS (TOF ES):
Found 268.1318, calculated for C15H19NO2Na (M+Na)
268.1313 (1.9 ppm).
((1S*,2S*)-1,2-Diphenylcyclopropyl)(piperidin-1-yl)-
methanone (15ed): This compound was obtained via Typical
procedure A employing phenylmagnesium bromide (9d) (3.0
M in diethyl ether), 135 ꢁL, 0.405 mmol, 1.35 equiv.) and (1ꢀ
phenylcyclopropꢀ2ꢀenꢀ1ꢀyl)(piperidinꢀ1ꢀyl)methanone (11e)
(68.0 mg, 0.30 mmol, 1.0 equiv.). The product was purified by
column chromatography on Silica gel eluting with hexꢀ
ane/EtOAc (mixture 3:1). The titled compound was obtained
((1S*,2S*)-1,2-
Diphenylcyclopropyl)(morpholino)methanone (15fd): This
compound was obtained via Typical procedure A employing
phenylmagnesium bromide (9d) (3.0 M in diethyl ether, 135
ꢁL, 0.405 mmol, 1.35 equiv.) and morpholino(1ꢀ
phenylcyclopropꢀ2ꢀenꢀ1ꢀyl)methanone (11f) (69.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
matography on Silica gel eluting with hexane/EtOAc (mixture
3:1). The titled compound was obtained as a colorless solid,
mp 138.0ꢀ139.9 oC, Rf 0.26. Yield 74.8 mg (0.243 mmol,
81%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ 7.41 – 7.12
(m, 10H), 3.83 – 3.65 (m, 1H), 3.59 – 3.43 (m, 1H), 3.21 –
3.14 (m, 1H), 3.12 – 3.05 (m, 1H), 3.05 – 2.97 (m, 3H), 2.95 –
2.87 (m, 1H), 2.29 (dd, J = 7.0, 5.7 Hz, 1H), 2.15 – 2.08 (m,
1H), 1.42 (dd, J = 9.2, 5.7 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 168.0, 140.6, 137.5, 129.0 (+, 2C), 128.6 (+, 2C),
127.1 (+, 2C), 127.0 (+), 126.8 (+), 125.4 ( +, 2C), 66.3 (ꢀ),
66.0 (ꢀ), 46.0 (ꢀ), 42.3 (ꢀ), 39.8, 31.0 (+), 23.3 (ꢀ); FTIR (KBr,
cmꢀ1): 3057, 3028, 3003, 2962, 2922, 2897, 2854, 1639, 1599,
1496, 1458, 1431, 1359, 1301, 1274, 1215, 1190, 1112, 1068,
1031, 977, 898, 850, 773, 731; HRMS (TOF ES): Found
308.1666, calculated for C20H22NO2 (M+H) 308.1651 (4.9
ppm).
o
as a colorless solid, mp 120.6ꢀ121.9 C, Rf 0.29. Yield 81.8
mg (0.268 mmol, 89%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.41 – 7.16 (m, 10H), 3.54 – 3.43 (m, 1H), 3.35 –
3.20 (m, 1H), 3.01 (dd, J = 9.2, 7.0 Hz, 1H), 2.98 – 2.91 (m,
1H), 2.88 – 2.81 (m, 1H), 2.26 (dd, J = 7.0, 5.6 Hz, 1H), 1.39
(dd, J = 9.2, 5.6 Hz, 1H), 1.38 – 1.30 (m, 1H), 1.27 – 1.18 (m,
2H), 1.16 – 1.05 (m, 1H), 0.90 – 0.80 (m, 1H), 0.33 – 0.20 (m,
1H); 13C NMR (126 MHz, CDCl3) δ 167.7, 141.1, 137.8,
128.7 (+, 2C), 128.2 (+, 2C), 127.0 (+, 2C), 126.5 (+), 126.4
(+), 125.4 (+, 2C), 46.4 (ꢀ), 42.8 (ꢀ), 40.0, 30.9 (+), 25.0 (ꢀ),
25.0 (ꢀ), 24.1 (ꢀ), 23.6 (ꢀ); FTIR (KBr, cmꢀ1): 3057, 3028,
3005, 2935, 2854, 1631, 1496, 1437, 1292, 1271, 1247, 1217,
1136, 1124, 1078, 1031, 1012, 974, 852, 773, 761, 731;
HRMS (TOF ES): Found 328.1682, calculated for
C21H23NONa (M+Na) 328.1677 (1.5 ppm).
((1S*,2S*)-1-Phenyl-2-vinylcyclopropyl)(piperidin-1-yl)-
methanone (15ee): This compound was obtained via Typical
procedure A employing vinylmagnesium bromide (9e) (1.0 M
in THF, 405 ꢁL, 0.405 mmol, 1.35 equiv.) and (1ꢀphenylꢀ
cyclopropꢀ2ꢀenꢀ1ꢀyl)(piperidinꢀ1ꢀyl)methanone (11e) (68.0
mg, 0.30 mmol, 1.0 equiv.). The product was purified by colꢀ
umn chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a viscous
colorless oil, Rf 0.29. Yield 66.0 mg (0.258 mmol, 86%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.33 – 7.27 (m, 2H),
7.23 – 7.16 (m, 3H), 5.49 – 5.39 (m, 1H), 5.29 (dd, J = 17.0,
1.6 Hz, 1H), 5.07 (dd, J = 10.2, 1.7 Hz, 1H), 3.75 – 3.66 (m,
Morpholino((1S*,2S*)-1-phenyl-2-vinylcyclopropyl)-
methanone (15fe): This compound was obtained via Typical
procedure A employing vinylmagnesium bromide (9e) (1.0 M
in THF, 405 ꢁL, 0.405 mmol, 1.35 equiv.) and morpholino(1ꢀ
phenylcyclopropꢀ2ꢀenꢀ1ꢀyl)methanone (15f) (69.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
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matography on Silica gel eluting with hexane/EtOAc (mixture
Page 18 of 29
1
2
3
4
5
6
7
8
3:1). The titled compound was obtained as a viscous colorless
oil, Rf 0.16. Yield 63.8 mg (0.248 mmol, 83%), dr >99:1. 1H
NMR (500 MHz, CDCl3) δ 7.36 – 7.28 (m, 2H), 7.25 – 7.20
(m, 1H), 7.18 – 7.14 (m, 2H), 5.51 – 5.38 (m, 1H), 5.30 (dd, J
= 17.0, 1.6 Hz, 1H), 5.12 (dd, J = 10.1, 1.6 Hz, 1H), 3.80 –
3.70 (m, 1H), 3.69 – 3.53 (m, 3H), 3.44 – 3.32 (m, 2H), 3.30 –
3.18 (m, 2H), 2.60 – 2.47 (m, 1H), 1.80 (dd, J = 6.2, 5.1 Hz,
1H), 1.18 (dd, J = 8.7, 5.1 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 169.2, 140.2, 136.8 (+), 129.0 (+, 2C), 126.8 (+),
125.3 (+, 2C), 116.3 (ꢀ), 66.8 (ꢀ), 66.7 (ꢀ), 46.3 (ꢀ), 42.6 (ꢀ),
36.6, 29.3 (+), 23.7 (ꢀ); FTIR (KBr, cmꢀ1): 3082, 3059, 3001,
2962, 2920, 2899, 2856, 1651, 1643, 1600, 1496, 1456, 1429,
1359, 1301, 1274, 1195, 1114, 1068, 1031, 985, 943, 908,
850, 758, 700; HRMS (TOF ES): Found 280.1309, calculated
for C16H19NO2Na (M+Na) 280.1313 (1.4 ppm).
(1S*,2S*)-N,N-diallyl-1-phenyl-2-vinylcyclopropane-1-
carboxamide (15ge): This compound was obtained via Typiꢀ
cal procedure A employing vinylmagnesium bromide (9e) (1.0
M in THF, 405 ꢁL, 0.405 mmol, 1.35 equiv.) and N,Nꢀdiallylꢀ
1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11g) (72.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
matography on Silica gel eluting with hexane/EtOAc (mixture
3:1). The titled compound was obtained as a viscous light yelꢀ
low oil, Rf 0.45. Yield 63.8 mg (0.239 mmol, 80%), dr >99:1.
1H NMR (500 MHz, CDCl3) δ 7.40 – 7.10 (m, 5H), 5.87 –
5.60 (m, 1H), 5.57 – 5.37 (m, 1H), 5.37 – 5.27 (m, 1H), 5.22 –
5.02 (m, 3H), 5.00 – 4.82 (m, 3H), 4.30 – 4.15 (m, 1H), 4.12 –
3.93 (m, 1H), 3.77 – 3.45 (m, 2H), 2.70 – 2.41 (m, 1H), 1.83
(dd, J = 6.2, 5.0 Hz, 1H), 1.14 (dd, J = 8.7, 5.0 Hz, 1H); 13C
NMR (126 MHz, CDCl3) δ 170.2, 140.5, 136.6 (+), 133.2 (+),
132.9 (+), 128.9 (+, 2C), 126.8 (+), 126.2 (+, 2C), 118.6 (ꢀ),
117.7 (ꢀ), 116.2 (ꢀ), 49.6 (ꢀ), 46.6 (ꢀ), 37.2, 28.4 (+), 23.2 (ꢀ);
FTIR (KBr, cmꢀ1): 3080, 3063, 3007, 2982, 1643, 1633, 1600,
1496, 1435, 1411, 1332, 1296, 1261, 1205, 1136, 1111, 1031,
993, 923, 758, 731, 700; HRMS (TOF ES): Found 290.1519,
calculated for C18H21NONa (M+Na) 290.1521 (0.7 ppm).
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14
15
16
17
18
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(1S*,2R*)-N,N-diallyl-2-methyl-1-phenylcyclopropane-
1-carboxamide (15ga): This compound was obtained via
Typical procedure A employing methylmagnesium bromide
(9a) (3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.)
and
N,Nꢀdiallylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(11g) (72.0 mg, 0.30 mmol, 1.0 equiv.). The product was puriꢀ
fied by column chromatography on Silica gel eluting with
hexane/EtOAc (mixture 6:1). The titled compound was obꢀ
tained as a viscous colorless oil, Rf 0.29. Yield 71.6 mg
(0.280 mmol, 94%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ
7.34 – 7.14 (m, 5H), 5.83 – 5.65 (m, 1H), 5.22 – 5.05 (m, 2H),
4.97 – 4.88 (m, 3H), 4.35 – 4.24 (m, 1H), 4.21 – 4.11 (m, 1H),
3.72 – 3.53 (m, 2H), 1.94 – 1.86 (m, 1H), 1.43 (dd, J = 6.3, 4.6
Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H), 0.91 (dd, J = 8.8, 4.7 Hz,
1H); 13C NMR (126 MHz, CDCl3) δ 170.9, 141.6, 133.1 (+),
128.8 (+, 3C), 126.4 (+), 126.4 (+, 2C), 118.5 (ꢀ), 117.8 (ꢀ),
49.5 (ꢀ), 46.7 (ꢀ), 35.4, 23.4 (ꢀ), 18.7 (+), 15.0 (+); FTIR
(KBr, cmꢀ1): 3078, 3005, 2980, 2958, 2928, 1643, 1633, 1600,
1496, 1454, 1435, 1410, 1332, 1300, 1280, 1263, 1209, 1193,
1138, 1112, 1095, 993, 923, 759, 731; HRMS (TOF ES):
Found 278.1536, calculated for C17H21NONa (M+Na)
278.1521 (5.4 ppm).
(1S*,2R*)-N-Methoxy-N,2-dimethyl-1-
phenylcyclopropane-1-carboxamide (15ha): This compoꢀ
und was obtained via Typical procedure A employing methylꢀ
magnesium bromide (9a) (3.0 M in diethyl ether, 135 ꢁL,
0.405 mmol, 1.35 equiv.) and NꢀmethoxyꢀNꢀmethylꢀ1ꢀphenylꢀ
cyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11h) (61.0 mg, 0.30 mmol,
1.0 equiv.). The product was purified by column chromatogꢀ
raphy on Silica gel eluting with hexane/EtOAc (mixture 3:1).
The titled compound was obtained as a viscous light yellow
oil, Rf 0.39. Yield 59.2 mg (0.270 mmol, 90%), dr >99:1. 1H
NMR (500 MHz, CDCl3) δ 7.34 – 7.14 (m, 5H), 3.12 (s, 3H),
3.05 (s (broad), 3H), 1.96 – 1.84 (m, 1H), 1.43 (dd, J = 6.4,
4.6 Hz, 1H), 1.16 (d, J = 6.3 Hz, 3H), 0.85 (s (broad), 1H);
13C NMR (126 MHz, CDCl3) δ 141.6, 128.5 (+, 2C), 127.5,
126.5 (+, 3C), 60.2, 35.7 (+), 33.3 (+), 22.0 (ꢀ), 18.4 (+), 14.5
(+); FTIR (KBr, cmꢀ1): 3059, 3001, 2962, 2931, 2874, 1660,
1651, 1600, 1496, 1442, 1410, 1365, 1172, 1122, 1101, 1074,
993, 908, 761; HRMS (TOF ES): Found 242.1165, calculated
for C13H17NO2Na (M+Na) 242.1157 (3.3 ppm).
(1S*,2S*)-N,N-Diallyl-1,2-diphenylcyclopropane-1-
carboxamide (15gd): This compound was obtained via Typiꢀ
cal procedure A employing phenylmagnesium bromide (9d)
(3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.) and
(E)-N,N-diethyl-2-phenylhex-3-enamide (16ab): A flame
dried Schlenk flask was charged with copper iodide (3.0 mg,
15.0 ꢁmol, 5.0 mol%) and freshly distilled dry dimethoxyeꢀ
thane (1.0 mL) under a nitrogen atmosphere. Ethylmagnesium
bromide (9b) (3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol,
N,Nꢀdiallylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(11g)
(72.0 mg, 0.30 mmol, 1.0 equiv.). The product was purified by
column chromatography on Silica gel eluting with hexꢀ
ane/EtOAc (mixture 6:1). The titled compound was obtained
o
o
as a colorless solid, mp 111.5ꢀ113.9 C, Rf 0.32. Yield 90.6
1.35 equiv.) was added dropwise at 0 C, and the mixture was
1
mg (0.285 mmol, 95%), dr 9:1. H NMR (500 MHz, CDCl3) δ
stirred for five minutes. N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ
1ꢀcarboxamide (11a) (65.0 mg, 0.30 mmol, 1.0 equiv.) was
then added dropwise as a solution in dry dimethoxyethane (1.0
mL). The reaction mixture was then stirred for 1 hr at room
temperature. Saturated aqueous ammonium chloride (1 mL)
was added slowly. The resulting solution was then diluted
with water and extracted with diethyl ether (3 x 5 mL). Comꢀ
bined organic layers were washed with brine, dried, filtered,
and concentrated. The product was purified by column chroꢀ
matography on Silica gel eluting with hexane/EtOAc (mixture
6:1). The titled compound was obtained as a viscous colorless
oil, Rf 0.26. Yield (56.4 mg, 0.230 mmol, 77%). 1H NMR
(500 MHz, CDCl3) δ 7.37 – 7.19 (m, 5H), 5.87 (dd, J = 15.4,
8.0 Hz, 1H), 5.51 (dt, J = 15.4, 6.3 Hz, 1H), 4.38 (d, J = 8.0
Hz, 1H), 3.55 – 3.44 (m, 1H), 3.38 – 3.14 (m, 3H), 2.11 – 1.99
7.56 – 7.15 (m, 10H), 5.20 – 5.09 (m, 1H), 4.85 (d, J = 10.2
Hz, 1H), 4.78 (d, J = 10.1 Hz, 1H), 4.74 (d, J = 17.1 Hz, 1H),
4.64 (d, J = 17.2 Hz, 1H), 4.50 – 4.36 (m, 1H), 4.12 – 4.02 (m,
1H), 3.99 – 3.87 (m, 1H), 3.37 – 3.29 (m, 1H), 3.14 (dd, J =
9.1, 6.9 Hz, 1H), 3.12 – 3.06 (m, 1H), 2.38 (dd, J = 6.9, 5.5
Hz, 1H), 1.30 (dd, J = 9.1, 5.5 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 169.0, 141.0, 136.9, 132.8 (+), 132.6 (+), 128.9 (+,
2C), 128.4 (+, 2C), 127.6 (+, 2C), 126.9 (+), 126.7 (+), 126.4
(+, 2C), 118.5 (ꢀ), 117.3 (ꢀ), 49.4 (ꢀ), 46.2 (ꢀ), 40.4, 29.2 (+),
22.2 (ꢀ); FTIR (KBr, cmꢀ1): 3084, 3063, 3028, 3010, 2910,
1643, 1622, 1600, 1494, 1454, 1442, 1435, 1411, 1300, 1284,
1269, 1215, 1180, 1076, 1031, 991, 922, 902, 765, 734;
HRMS (TOF ES): Found 340.1675, calculated for
C22H23NONa (M+Na) 340.1677 (0.6 ppm).
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(+), 14.7 (+), 12.7 (+), 12.6 (+); FTIR (KBr, cmꢀ1): 3028,
(m, 2H), 1.11 (t, J = 7.1 Hz, 6H), 1.07 (t, J = 7.1 Hz, 3H), 0.97
(t, J = 7.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 171.7,
140.2, 133.6 (+), 129.0 (+), 128.8 (+, 2C), 128.0 (+, 2C),
126.9 (+), 52.5 (+), 41.9 (ꢀ), 40.4 (ꢀ), 25.6 (ꢀ), 14.6 (+), 13.6
(+), 13.0 (+); FTIR (KBr, cmꢀ1): 3059, 3026, 2966, 2931,
2872, 1639, 1600, 1492, 1479, 1454, 1427, 1379, 1361, 1311,
1276, 1253, 1219, 1138, 1095, 1072, 966, 783, 752; HRMS
(TOF ES): Found 246.1852, calculated for C16H24NO (M+H)
246.1858 (2.4 ppm).
3003, 2968, 2933, 2872, 1633, 1496, 1471, 1456, 1425, 1379,
1363, 1319, 1294, 1276, 1220, 1151, 1128, 1101, 1080, 1066,
868, 759, 732, 700; HRMS (TOF ES): Found 255.1586, calꢀ
culated for C15H20DNONa (M+Na) 255.1584 (0.8 ppm).
1
2
3
4
5
6
7
8
(1S*,2S*,3S*)-N,N-Diethyl-1-phenyl-2-
vinylcyclopropane-1-carboxamide-3-d (18ae): This compoꢀ
und was obtained via Typical procedure C employing vinylꢀ
magnesium bromide (9e) (1.0 M in THF, 405 ꢁL, 0.405 mmol,
1.35 equiv.), N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxꢀ
amide (11a) (65.0 mg, 0.30 mmol, 1.0 equiv.), and quenching
with methanolꢀd4 (19.0 ꢁL, 16.5 mg, 0.45 mmol, 1.50 equiv.).
The product was purified by column chromatography on Silica
gel eluting with hexane/EtOAc (mixture 3:1). The titled comꢀ
pound was obtained as a viscous colorless oil, Rf 0.35. Yield
63.2 mg (0.259 mmol, 86%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.32 – 7.27 (m, 2H), 7.24 – 7.17 (m, 3H), 5.41 (ddd,
J = 17.0, 10.1, 9.0 Hz, 1H), 5.28 (dd, J = 17.0, 1.7 Hz, 1H),
5.05 (dd, J = 10.1, 1.8 Hz, 1H), 3.61 – 3.38 (m, 2H), 3.17 (dq,
J = 13.9, 7.0 Hz, 1H), 3.01 (dq, J = 14.2, 7.1 Hz, 1H), 2.55
(dd, J = 8.9 Hz, 1H), 1.09 (t, J = 7.1 Hz, 3H), 1.08 (d, J = 8.9
Hz, 1H), 0.55 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 169.7, 140.9, 136.7 (+), 128.8 (+, 2C), 126.6 (+),
126.0 (+, 2C), 115.8 (ꢀ), 41.3 (ꢀ), 39.3 (ꢀ), 37.2, 28.2 (+), 23.1
(+, t 1:1:1, J = 25.2 Hz), 12.7 (+), 12.4 (+); FTIR (KBr, cmꢀ1):
3082, 3059, 2974, 2935, 2874, 1633, 1496, 1456, 1444, 1427,
1381, 1361, 1315, 1276, 1219, 1128, 991, 902, 756, 700;
HRMS (TOF ES): Found 245.1770, calculated for C16H21DNO
(M+H) 245.1764 (2.4 ppm).
9
1-((1S*,2R*)-2-Methyl-1-phenylcyclopropyl)ethan-1-one
(17): Methylmagnesium bromide (9a) (130 ꢁL, 3.0 M (diethyl
ether), 0.40 mmol, 2.0 equiv.) was added dropwise to a stirred
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
solution
of
(1S*,2R*)ꢀNꢀmethoxyꢀN,2ꢀdimethylꢀ1ꢀ
phenylcyclopropaneꢀ1ꢀcarboxamide (15ha) (44.0 mg, 0.20
mmol, 1.0 equiv.) in dry dimethoxyethane. The reaction mixꢀ
o
ture was stirred at 40 C for 18 hours. After cooling to room
temperature, saturated aqueous ammonium chloride (1 mL)
was added dropwise. The resulting solution was diluted with
water and extracted with diethyl ether (3 x 5 mL). Combined
organic layers were dried, filtered, and evaporated. The prodꢀ
uct was purified by column chromatography on Silica gel elutꢀ
ing with hexane/EtOAc (mixture 6:1). The titled compound
was obtained as a viscous colorless oil, Rf 0.32. Yield 21.2
mg (0.122 mmol, 61%). 1H NMR (500 MHz, CDCl3) δ 7.34 –
7.16 (m, 5H), 1.90 (s, 3H), 1.70 (ddq, J = 8.7, 7.2, 6.2 Hz,
1H), 1.58 (dd, J = 7.1, 4.0 Hz, 1H), 1.12 (d, J = 6.2 Hz, 3H),
1.01 (dd, J = 8.7, 4.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
206.9, 142.6, 130.5 (+, 2C), 128.8 (+, 2C), 127.4 (+), 43.3,
30.8 (+), 25.5 (+), 22.0 (ꢀ), 12.3 (+); FTIR (KBr, cmꢀ1): 3022,
3001, 2955, 2928, 2874, 1691, 1600, 1492, 1456, 1444, 1435,
1361, 1280, 1165, 1132, 1097, 1074, 1024, 979, 758; HRMS
(TOF ES): Found 192.1386, calculated for C12H18NO
(M+NH4) 192.1388 (1.0 ppm).
(1s,2R*,3S*)-N,N-Diethyl-2,3-dimethyl-1-
phenylcyclopropane-1-carboxamide (19aa):
This comꢀ
pound was obtained via Typical procedure C employing
methylmagnesium bromide (9a) (135 ꢁL, (3.0 M in diethyl
ether), 0.405 mmol, 1.35 equiv.), N,Nꢀdiethylꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0 mg, 0.30
mmol, 1.0 equiv.), and quenching with methyl iodide (28.0
ꢁL, 64.0 mg, 0.45 mmol, 1.50 equiv.). The product was puriꢀ
fied by column chromatography on Silica gel eluting with
hexane/EtOAc (mixture 3:1). The titled compound was obꢀ
tained as a viscous colorless oil, Rf 0.32. Yield 63.2 mg
(0.258 mmol, 86%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ
7.28 – 7.23 (m, 2H), 7.21 – 7.12 (m, 3H), 3.37 (q, J = 7.2 Hz,
2H), 3.32 (q, J = 7.1 Hz, 2H), 1.47 (s, 2H), 1.21 (d, J = 6.4 Hz,
6H), 1.11 (d, J = 7.1 Hz, 3H), 0.59 (t, J = 7.1 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 169.5, 143.0, 128.6 (+, 2C), 126.0
(+), 125.7 (+, 2C), 41.4 (ꢀ), 38.4 (ꢀ), 35.9, 25.1 (+, 2C), 13.0
(+), 12.6 (+), 10.0 (+, 2C); FTIR (KBr, cmꢀ1): 3057, 3003,
2970, 2931, 2872, 1633, 1496, 1458, 1444, 1423, 1379, 1363,
1346, 1319, 1298, 1278, 1238, 1220, 1155, 1116, 1093, 1078,
756, 732; HRMS (TOF ES): Found 268.1669, calculated for
C16H23NONa (M+Na) 268.1677 (3.0 ppm).
(1S*,2R*,3S*)-N,N-Diethyl-2-methyl-1-
phenylcyclopropane-1-carboxamide-3-d (18aa), Typical
Procedure C: Flame dried Schlenk flask was charged with
copper iodide (3.0 mg, 15.0 ꢁmol, 5.0 mol%) and freshly disꢀ
tilled dry dimethoxyethane (1.0 mL) under a nitrogen atmosꢀ
phere. Methylmagnesium bromide (9a) (3.0 M in diethyl
ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.) was added dropwise
at 0 oC, and the mixture was stirred for 5 min at the same temꢀ
perature.
N,NꢀDiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxamide (11a) (65.0 mg, 0.30 mmol, 1.0 equiv.) was then
added dropwise as a solution in dry dimethoxyethane (1.0
mL). After 5 min of stirring, methanolꢀd4 (19.0 ꢁL, 16.5 mg,
0.45 mmol, 1.50 equiv.) was added dropwise and stirred for 15
o
min at 0 C. The reaction was then allowed to warm to room
temperature over 15 minutes before saturated aqueous ammoꢀ
nium chloride (1 mL) was added. The resulting solution was
then diluted with water and extracted with diethyl ether (3 x 5
mL). Combined organic layers were washed with brine, dried,
filtered, and evaporated. The product was purified by column
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a viscous
colorless oil, Rf 0.32. Yield (68.4 mg, 0.294 mmol, 98%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.32 – 7.23 (m, 2H),
7.22 – 7.12 (m, 3H), 3.63 – 3.51 (m, 2H), 3.18 (dq, J = 14.0,
7.0 Hz, 1H), 3.07 (dq, J = 14.1, 7.0 Hz, 1H), 1.88 (dq, J = 8.8,
6.3 Hz, 1H), 1.13 (d, J = 6.3 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H),
0.84 (d, J = 8.7 Hz, 1H), 0.55 (t, J = 7.1 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 170.5, 142.0, 128.7 (+, 2C), 126.2 (+,
3C), 41.4 (ꢀ), 39.3 (ꢀ), 35.4, 23.3 (+, t 1:1:1, J = 24.5 Hz), 18.2
(1S*,2S*,3R*)-N,N-Diisopropyl-2-methyl-1-phenyl-3-
vinylcyclopropane-1-carboxamide (19be): This compound
was obtained via Typical procedure C employing vinylmagneꢀ
sium bromide (9e) (1.0 M in THF, 405 ꢁL 0.405 mmol, 1.35
equiv.),
N,Nꢀdiisopropylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxamide (11b) (73.0 mg, 0.30 mmol, 1.0 equiv.), and
quenching with methyl iodide (28.0 ꢁL, 64.0 mg, 0.45 mmol,
1.50 equiv.). The product was purified by column chromatogꢀ
raphy on Silica gel eluting with hexane/EtOAc (mixture 3:1).
The titled compound was obtained as a yellow solid, mp 94.4ꢀ
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o
96.0 C, Rf 0.61. Yield 69.4 mg (0.243 mmol, 81%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.30 – 7.27 (m, 4H),
7.22 – 7.15 (m, 1H), 5.95 – 5.74 (m, 1H), 5.22 (d, J = 17.0 Hz,
1H), 5.13 (dd, J = 10.2, 1.9 Hz, 1H), 4.14 (hept, J = 6.6 Hz,
1H), 3.19 (hept, J = 6.8 Hz, 1H), 2.08 (s (broad), 1H), 1.76 (s
(broad), 1H), 1.42 (t, J = 6.5 Hz, 6H), 1.33 (d, J = 6.6 Hz, 3H),
0.78 (s (broad), 3H), 0.64 (s (broad), 3H); 13C NMR (126
MHz, CDCl3) δ 168.3, 142.0, 135.1 (+), 128.7 (+, 2C), 126.4
(+), 126.2 (+, 2C), 115.8 (ꢀ, broad), 48.9 (+), 45.8 (+), 40.8
(broad), 35.0 (+, broad), 26.2 (+, broad), 20.8 (+), 20.6 (+),
20.4 (+), 20.1 (+), 11.4 (+); FTIR (KBr, cmꢀ1): 3080, 3059,
3001, 2962, 2929, 2872, 1633, 1494, 1435, 1369, 1336, 1211,
1155, 1118, 1039, 987, 900, 734; HRMS (TOF ES): Found
286.2162, calculated for C19H28NO (M+H) 286.2171 (3.1
ppm).
1101, 1078, 995, 908, 817; HRMS (TOF ES): Found
294.1840, calculated for C18H25NONa (M+Na) 294.1834 (2.0
ppm).
1
2
3
4
5
6
7
8
((1S*,2S*,3S*)-2-Allyl-1,3-
diphenylcyclopropyl)(morpholino)methanone (20fd): This
compound was obtained via Typical procedure C employing
phenylmagnesium bromide (9d) (3.0 M in diethyl ether, 135
ꢁL 0.405 mmol, 1.35 equiv.), morpholino(1ꢀphenylcyclopropꢀ
2ꢀenꢀ1ꢀyl)methanone (11f) (69.0 mg, 0.30 mmol, 1.0 equiv.),
and quenching with allyl bromide (39.0 ꢁL, 55.0 mg, 0.45
mmol, 1.50 equiv.). The product was purified by column
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a colorꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
less solid, mp 102.4ꢀ103.5 C, Rf 0.29. Yield 91.2 mg (0.262
mmol, 87%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ 7.45 –
7.18 (m, 10H), 5.95 – 5.69 (m, 1H), 4.96 (dd, J = 17.2, 1.9 Hz,
1H), 4.88 (dd, J = 10.2, 1.9 Hz, 1H), 3.80 – 3.66 (m, 1H), 3.58
– 3.49 (m, 1H), 3.48 – 3.33 (m, 2H), 3.10 – 2.87 (m, 4H), 3.03
(d, J = 9.9 Hz, 1H), 2.60 – 2.46 (m, 1H), 2.44 – 2.31 (m, 1H),
1.59 – 1.39 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 167.8,
141.5, 137.6 (+), 136.4, 128.9 (+, 2C), 128.7 (+, 2C), 128.2 (+,
2C), 126.7 (+), 126.6 (+), 125.5 (+, 2C), 114.9 (ꢀ), 66.0 (ꢀ),
65.4 (ꢀ), 46.1 (ꢀ), 41.7 (ꢀ), 38.4, 35.9 (+), 33.3 (+), 28.7 (ꢀ);
FTIR (KBr, cmꢀ1): 3059, 3028, 3001, 2970, 2920, 2899, 2856,
1639, 1600, 1498, 1456, 1427, 1359, 1300, 1273, 1222, 1192,
1114, 1070, 1030, 999, 968, 912, 839; HRMS (TOF ES):
Found 370.1765, calculated for C23H25NO2Na (M+Na)
370.1783 (4.9 ppm).
((1S*,2S*,3S*)-2-Methyl-1,3-
diphenylcyclopropyl)(piperidin-1-yl)methanone
(19ed):
This compound was obtained via Typical procedure C emꢀ
ploying phenylmagnesium bromide (9d) (3.0 M in diethyl
ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.), (1ꢀphenylcyclopropꢀ
2ꢀenꢀ1ꢀyl)(piperidinꢀ1ꢀyl)methanone (11e) (68.0 mg, 0.30
mmol, 1.0 equiv.), and quenching with methyl iodide (28.0
ꢁL, 64.0 mg, 0.45 mmol, 1.50 equiv.). The product was puriꢀ
fied by column chromatography on Silica gel eluting with
hexane/EtOAc (mixture 3:1). The titled compound was obꢀ
o
tained as a colorless solid, mp 121.1ꢀ125.4 C, Rf 0.42. Yield
83.4 mg (0.261 mmol, 87%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.36 – 7.32 (m, 4H), 7.30 – 7.27 (m, 4H), 7.24 –
7.19 (m, 2H), 3.58 – 3.46 (m, 2H), 3.11 – 2.98 (m, 1H), 2.89
(d, J = 10.0 Hz, 1H), 2.87 – 2.82 (m, 1H), 1.68 (dq, J = 9.9,
6.7 Hz, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.44 – 1.34 (m, 2H),
1.34 – 1.23 (m, 2H), 0.87 – 0.73 (m, 1H), 0.51 – 0.39 (m, 1H);
13C NMR (126 MHz, CDCl3) δ 167.8, 142.5, 136.9, 129.4 (+,
2C), 128.8 (+, 2C), 127.9 (+, 2C), 126.4 (+), 126.2 (+), 125.6
(+, 2C), 46.7 (ꢀ), 42.3 (ꢀ), 38.3, 34.8 (+), 30.3 (+), 25.1 (ꢀ),
24.8 (ꢀ), 24.3 (ꢀ), 10.0 (+); FTIR (KBr, cmꢀ1): 3057, 3026,
2935, 2854, 1631, 1496, 1435, 1384, 1367, 1352, 1294, 1276,
1251, 1219, 1199, 1126, 1060, 1031, 1001, 852, 763, 744,
727, 700; HRMS (TOF ES): Found 342.1845, calculated for
C22H25NONa (M+Na) 342.1834 (3.2 ppm).
(1S*,2S*,3R*)-N,N,2-Triallyl-1-phenyl-3-
vinylcyclopropane-1-carboxamide (20ge): This compound
was obtained via Typical procedure C employing vinylꢀ
magnesium bromide (9e) (1.0 M in THF, 405 ꢁL 0.405 mmol,
1.35
equiv.),
N,Nꢀdiallylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxamide (11g) (72.0 mg, 0.30 mmol, 1.0 equiv.), and
quenching with allyl bromide (39.0 ꢁL, 55.0 mg, 0.45 mmol,
1.50 equiv.). The product was purified by column chromatogꢀ
raphy on Silica gel eluting with hexane/EtOAc (mixture 6:1).
The titled compound was obtained as a viscous colorless oil,
Rf 0.45. Yield 70.2 mg (0.228 mmol, 76%), dr >99:1. 1H
NMR (500 MHz, CDCl3) δ 7.42 – 7.15 (m, 5H), 6.09 – 5.88
(m, 1H), 5.82 – 5.63 (m, 2H), 5.34 (dd, J = 16.9, 1.7 Hz, 1H),
5.18 (dd, J = 10.3, 1.8 Hz, 1H), 5.13 (dd, J = 10.2, 1.4 Hz,
1H), 5.09 (dd, J = 17.2, 1.6 Hz, 2H), 5.00 (dd, J = 10.3, 1.9
Hz, 1H), 4.94 – 4.90 (m, 3H), 4.11 – 3.97 (m, 1H), 3.94 – 3.66
(m, 3H), 2.81 – 2.65 (m, 1H), 2.48 – 2.35 (m, 1H), 2.33 – 2.18
(m, 1H), 1.61 – 1.50 (m, 1H); 13C NMR (126 MHz, CDCl3) δ
169.0, 141.2, 137.4 (+), 133.7 (+), 133.4 (+), 132.9 (+), 128.9
(+, 2C), 126.7 (+), 126.0 (+, 2C), 118.7 (ꢀ), 117.8 (ꢀ), 117.2 (ꢀ
), 115.3 (ꢀ), 50.0 (ꢀ), 46.0 (ꢀ), 38.8, 33.3 (+), 32.9 (+), 30.6 (ꢀ);
FTIR (KBr, cmꢀ1): 3078, 3003, 2980, 2920, 1643, 1631, 1600,
1496, 1450, 1435, 1410, 1330, 1298, 1282, 1269, 1205, 1192,
1128, 993, 922, 910, 759, 734; HRMS (TOF ES): Found
330.1822, calculated for C21H25NONa (M+Na) 330.1834 (3.6
ppm).
(1R*,2S*,3R*)-2-Allyl-N,N-diethyl-3-methyl-1-
phenylcyclopropane-1-carboxamide (20aa):
This comꢀ
pound was obtained via Typical procedure C employing
methylmagnesium bromide (9a) (3.0 M in diethyl ether, 135
ꢁL, 0.405 mmol, 1.35 equiv.), N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ
2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0 mg, 0.30 mmol, 1.0 equiv.),
and quenching with allyl bromide (39.0 ꢁL, 55.0 mg, 0.45
mmol, 1.50 equiv.). The product was purified by column
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 6:1). The titled compound was obtained as a viscous
colorless oil, Rf 0.38. Yield 70.6 mg (0.260 mmol, 87%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.14 (m, 5H),
6.09 – 5.85 (m, 1H), 5.09 (dd, J = 17.2, 1.9 Hz, 1H), 4.99 (dd,
J = 10.2, 2.0 Hz, 1H), 3.55 – 3.36 (m, 2H), 3.34 – 3.16 (m,
2H), 2.74 – 2.55 (m, 1H), 2.26 – 2.09 (m, 1H), 1.82 – 1.68 (m,
1H), 1.36 – 1.25 (m, 1H), 1.21 (d, J = 6.5 Hz, 3H), 1.11 (t, J =
7.1 Hz, 3H), 0.56 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 169.4, 142.7, 138.4 (+), 128.7 (+, 2C), 126.1 (+),
125.9 (+, 2C), 114.6 (ꢀ), 41.5 (ꢀ), 38.6 (ꢀ), 36.1, 31.2 (+), 29.8
(ꢀ), 22.9 (+), 12.9 (+), 12.6 (+), 9.9 (+); FTIR (KBr, cmꢀ1):
3061, 3003, 2972, 2933, 2874, 1633, 1600, 1496, 1458, 1423,
1379, 1363, 1346, 1319, 1298, 1278, 1240, 1220, 1155, 1120,
(1R*,2S*,3R*)-2-Benzyl-N,N-diethyl-3-methyl-1-
phenylcyclopropane-1-carboxamide (21aa):
This comꢀ
pound was obtained via Typical procedure C employing
methylmagnesium bromide (9a) (3.0 M in diethyl ether, 135
ꢁL, 0.405 mmol, 1.35 equiv.), N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ
2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0 mg, 0.30 mmol, 1.0 equiv.),
and quenching with benzyl bromide (54.0 ꢁL, 77.0 mg, 0.45
20
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The Journal of Organic Chemistry
133.9 (+), 128.9 (+, 2C), 128.8 (+, 2C), 128.4 (+, 2C), 126.5
mmol, 1.50 equiv.). The product was purified by column
1
2
3
4
5
6
7
8
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 6:1). The titled compound was obtained as a colorꢀ
less solid, mp 86.0ꢀ86.9 C, Rf 0.29. Yield 78.8 mg (0.245
(+), 125.9 (+), 125.6 (+, 2C), 117.4 (ꢀ), 46.8 (ꢀ), 46.1 (ꢀ), 40.0,
36.1 (+), 33.1 (+), 32.1 (ꢀ), 26.3 (ꢀ), 24.1 (ꢀ); FTIR (KBr, cmꢀ
1): 3082, 3059, 3024, 2972, 2874, 1633, 1600, 1494, 1450,
1419, 1340, 1249, 1222, 1190, 1170, 1124, 1112, 1080, 1031,
983, 910, 758, 736; HRMS (TOF ES): Found 354.1834, calꢀ
culated for C23H25NONa (M+Na) 354.1834 (3.1 ppm).
o
mmol, 82%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ 7.44 –
7.08 (m, 10H), 3.54 (dq, J = 14.8, 7.5 Hz, 1H), 3.47 (dq, J =
14.2, 7.1 Hz, 1H), 3.41 (dd, J = 15.6, 4.5 Hz, 1H), 3.32 – 3.17
(m, 2H), 2.76 (dd, J = 15.6, 9.9 Hz, 1H), 1.88 (dq, J = 9.5, 6.5
Hz, 1H), 1.52 – 1.43 (m, 1H), 1.27 (d, J = 6.5 Hz, 3H), 1.15 (t,
J = 7.1 Hz, 3H), 0.57 (t, J = 7.1 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 169.5, 142.6, 142.3, 128.7 (+, 2C), 128.6 (+,
2C), 128.4 (+, 2C), 126.2 (+), 125.8 (+, 3C), 41.5 (ꢀ), 38.6 (ꢀ),
36.3, 33.6 (+), 31.3 (ꢀ), 22.6 (+), 12.9 (+), 12.7 (+), 10.2 (+);
FTIR (KBr, cmꢀ1): 3082, 3059, 3024, 2970, 2933, 2874, 1633,
1600, 1494, 1454, 1423, 1379, 1363, 1346, 1319, 1298, 1278,
1240, 1220, 1153, 1112, 1103, 1078, 1030, 947, 864; HRMS
(TOF ES): Found 344.1995, calculated for C22H27NONa
(M+Na) 344.1990 (1.5 ppm).
(1R*,2S*,3R*)-2-Benzyl-N,N-diethyl-1,3-
dimethylcyclopropane-1-carboxamide (21ka): This comꢀ
pound was obtained via Typical procedure C employing
methylmagnesium bromide (9a) (3.0 M in diethyl ether, 326
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢁL,
0.979
mmol,
1.35
equiv.),
N,Nꢀdiethylꢀ1ꢀ
methylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11k)23 (100 mg, 1.0
equiv., 0.65 mmol), and quenching with benzyl bromide (156
ꢁL, 223 mg, 1.31 mmol, 2.00 equiv.). The product was puriꢀ
fied by column chromatography on Silica gel eluting with
chloroform. The titled compound was obtained as a colorless
oil, Rf 0.27 (CHCl3). Yield 78.8 mg (0.245 mmol, 82%), dr
>99:1. 1H NMR (600 MHz, CDCl3) δ 7.32 – 7.26 (m, 4H),
7.17 (t, J = 6.8 Hz, 1H), 3.69 (dq, J = 14.2, 7.1 Hz, 1H), 3.52
(dq, J = 14.3, 7.2 Hz, 1H), 3.46 (dq, J = 14.2, 7.1 Hz, 1H),
3.33 – 3.24 (m, 2H), 2.47 (dd, J = 15.8, 9.4 Hz, 1H), 1.32 (s,
3H), 1.24 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1.08 (d,
J = 4.7 Hz, 4H); 13C NMR (151 MHz, CDCl3) δ 171.4, 142.5,
128.4 (+, 2C), 128.2 (+, 2C), 125.6 (+), 41.1 (ꢀ), 38.0 (ꢀ), 31.0
(ꢀ), 29.0 (+), 27.4, 24.7 (+), 23.2 (+), 14.3 (+), 12.7 (+), 10.5
(+); FTIR (NaCl, cmꢀ1): 3117, 3021, 2970, 2831, 1631, 1465,
1419, 1251, 1122 1095, 732, 628; HRMS (TOF ES): found
282.1833, calculated for C17H25NO (M+Na) 282.1834 (0.4
ppm).
(1S*,2S*,3S*)-N,N,2-Tribenzyl-1,3-
diphenylcyclopropane-1-carboxamide (21cd): This compoꢀ
und was obtained via Typical procedure C employing pheꢀ
nylmagnesium bromide (9d) (3.0 M in diethyl ether, 135 ꢁL,
0.405 mmol, 1.35 equiv.), N,Nꢀdibenzylꢀ1ꢀphenylcyclopropꢀ2ꢀ
eneꢀ1ꢀcarboxamide (11c) (102 mg, 0.30 mmol, 1.0 equiv.),
and quenching with benzyl bromide (54.0 ꢁL, 77.0 mg, 0.45
mmol, 1.50 equiv.). The product was purified by column
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 9:1). The titled compound was obtained as a colorꢀ
o
less solid, mp 143.5ꢀ146.1 C, Rf 0.38. Yield 120 mg (0.236
mmol, 79%), dr 15:1. 1H NMR (500 MHz, CDCl3) δ 7.58 –
7.47 (m, 2H), 7.40 – 6.87 (m, 21H), 6.28 – 6.12 (m, 2H), 4.95
(d, J = 14.0 Hz, 1H), 4.73 (d, J = 15.6 Hz, 1H), 3.80 (dd, J =
15.2, 4.9 Hz, 1H), 3.78 (d, J = 14.0 Hz, 1H), 3.68 (d, J = 15.6
Hz, 1H), 3.20 (d, J = 9.9 Hz, 1H), 2.99 (dd, J = 15.2, 9.0 Hz,
1H), 1.67 (ddd, J = 9.9, 9.0, 4.9 Hz, 1H); 13C NMR (126
MHz, CDCl3) δ 170.0, 142.2, 142.1, 136.6, 136.6, 135.6,
130.0 (+, 2C), 129.1 (+, 2C), 128.8 (+, 2C), 128.7 (+, 2C),
128.5 (+, 2C), 128.3 (+, 2C), 128.3 (+, 2C), 128.2 (+, 2C),
127.9 (+, 2C), 127.5 (+), 127.3 (+, 2C), 127.2 (+), 127.0 (+),
126.3 (+), 125.7 (+), 50.3 (ꢀ), 46.8 (ꢀ), 39.3, 36.8 (+), 32.3 (+),
30.5 (ꢀ); FTIR (KBr, cmꢀ1): 3084, 3061, 3028, 2929, 2914,
2862, 1952, 1880, 1809, 1643, 1633, 1600, 1494, 1454, 1417,
1361, 1329, 1265, 1209, 1078, 1030, 1003, 958, 943, 916,
842, 823, 767, 732, 700; HRMS (TOF ES): Found 530.2451,
calculated for C37H33NONa (M+Na) 530.2460 (1.7 ppm).
(1R*,2S*,3S*)-N,N-Diethyl-2-methyl-1-phenyl-3-
(trimethylsilyl)cyclopropane-1-carboxamide (22aa): This
compound was obtained via Typical procedure C employing
methylmagnesium bromide (9a) (3.0 M in diethyl ether, 135
ꢁL, 0.405 mmol, 1.35 equiv.), N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ
2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0 mg, 0.30 mmol, 1.0 equiv.),
and quenching with chlorotrimethylsilane (57.0 ꢁL, 49.0 mg,
0.45 mmol, 1.50 equiv.). The product was purified by column
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 6:1). The titled compound was obtained as a colorꢀ
o
less solid, mp 94.9ꢀ96.3 C, Rf 0.48. Yield 65.4 mg (0.215
mmol, 72%), dr >99:1. 1H NMR (500 MHz, CDCl3) δ 7.30 –
7.13 (m, 5H), 3.70 – 3.50 (m, 2H), 3.17 – 2.92 (m, 2H), 2.19
(dq, J = 10.6, 6.4 Hz, 1H), 1.17 (d, J = 6.5 Hz, 3H), 1.09 (t, J
= 7.0 Hz, 3H), 0.48 (t, J = 7.1 Hz, 3H), 0.15 (s, 9H), 0.00 (d, J
= 10.6 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 170.1, 144.0,
128.7 (+, 2C), 126.1 (+, 2C), 126.0 (+), 41.5 (ꢀ), 40.0, 39.2 (ꢀ),
26.1 (+), 21.9 (+), 13.6 (+), 12.8 (+), 12.7 (+), 1.3 (+, 3C);
FTIR (KBr, cmꢀ1): 3053, 3007, 2970, 2945, 2895, 2874, 1627,
1599, 1462, 1444, 1427, 1373, 1261, 1240, 1155, 1101, 1053,
1022, 952, 858, 837, 802, 742, 702; HRMS (TOF ES): Found
326.1902, calculated for C18H29NOSiNa (M+Na) 326.1916
(4.3 ppm).
((1S*,2S*,3R*)-2-Benzyl-1-phenyl-3-
vinylcyclopropyl)(pyrrolidin-1-yl)methanone (21de): This
compound was obtained via Typical procedure C employing
vinylmagnesium bromide (9e) (1.0 M in THF, 405 ꢁL, 0.405
mmol, 1.35 equiv.), (1ꢀphenylcyclopropꢀ2ꢀenꢀ1ꢀyl)(pyrrolidinꢀ
1ꢀyl)methanone (11d) (64.0 mg, 0.30 mmol, 1.0 equiv.), and
quenching with benzyl bromide (54.0 ꢁL, 77.0 mg, 0.45
mmol, 1.50 equiv.). The product was purified by column
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a viscous
colorless oil, Rf 0.26. Yield 78.2 mg (0.236 mmol, 79%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.14 (m, 10H),
5.98 – 5.70 (m, 1H), 5.37 (dd, J = 17.0, 1.8 Hz, 1H), 5.20 (dd,
J = 10.3, 1.8 Hz, 1H), 3.62 – 3.48 (m, 2H), 3.45 (dd, J = 15.3,
5.2 Hz, 1H), 3.35 – 3.23 (m, 1H), 2.96 – 2.85 (m, 2H), 2.50
(dd, J = 10.2, 9.2 Hz, 1H), 1.85 – 1.71 (m, 2H), 1.71 – 1.61
(m, 3H); 13C NMR (126 MHz, CDCl3) δ 168.2, 141.9, 140.9,
(1R*,2R*,3S*)-N,N-Diethyl-2-methyl-1-phenyl-3-
propionylcyclopropane-1-carboxamide (23aa): This comꢀ
pound was obtained via Typical procedure C employing
methylmagnesium bromide (9a) (3.0 M in diethyl ether, 135
ꢁL, 0.405 mmol, 1.35 equiv.), N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ
2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0 mg, 0.30 mmol, 1.0 equiv.),
and quenching with propionyl chloride (40.0 ꢁL, 42.0 mg,
0.45 mmol, 1.50 equiv.). The product was purified by column
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The Journal of Organic Chemistry
chromatography on Silica gel eluting with hexane/EtOAc
Page 22 of 29
126.8 (+), 126.6 (+, 2C), 46.9 (ꢀ), 46.3, 46.2 (ꢀ), 40.8 (+), 38.4
(ꢀ), 35.4 (+), 25.7 (ꢀ), 23.9 (ꢀ), 8.3 (+); FTIR (KBr, cmꢀ1):
3057, 3028, 2974, 2947, 2875, 1712, 1631, 1579, 1496, 1448,
1431, 1373, 1340, 1265, 1251, 1224, 1190, 1168, 1128, 1095,
1080, 1033, 962, 914, 869, 842, 771, 732, 700; HRMS (TOF
ES): Found 370.1771, calculated for C23H25NO2Na (M+Na)
370.1783 (3.2 ppm).
1
2
3
4
5
6
7
8
(mixture 3:1). The titled compound was obtained as a viscous
colorless oil, Rf 0.23. Yield 68.0 mg (0.237 mmol, 79%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.34 – 7.29 (m, 4H),
7.26 – 7.21 (m, 1H), 3.41 (dq, J = 14.1, 7.1 Hz, 1H), 3.31 –
3.22 (m, 2H), 3.18 (dq, J = 14.1, 7.2 Hz, 1H), 2.79 (dq, J =
17.4, 7.4 Hz, 1H), 2.57 (dq, J = 17.3, 7.3 Hz, 1H), 2.29 (d, J =
9.0 Hz, 1H), 2.03 (dq, J = 8.9, 6.6 Hz, 1H), 1.49 (d, J = 6.6
Hz, 3H), 1.12 (t, J = 7.3 Hz, 3H), 1.10 (t, J = 7.1 Hz, 1H), 0.57
(t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 207.5,
167.3, 140.9, 129.0 (+, 2C), 127.1 (+), 126.4 (+, 2C), 43.7,
41.5 (ꢀ), 38.9 (ꢀ), 38.8 (ꢀ), 37.7 (+), 28.1 (+), 12.9 (+), 12.5 (+),
10.4 (+), 8.2 (+); FTIR (KBr, cmꢀ1): 3059, 2974, 2935, 2875,
1703, 1639, 1633, 1494, 1462, 1444, 1427, 1381, 1361, 1317,
1298, 1278, 1219, 1155, 1122, 1105, 1082, 1066, 1041, 904,
850, 833, 759, 700; HRMS (TOF ES): Found 310.1800, calꢀ
culated for C18H25NO2Na (M+Na) 310.1783 (5.5 ppm).
(1R*,2S*,3S*)-N,N-Diethyl-2-iodo-3-methyl-1-
phenylcyclopropane-1-carboxamide (24aa):
This comꢀ
9
pound was obtained via Typical procedure C employing
methylmagnesium bromide (9a) (3.0 M in diethyl ether, 135
ꢁL, 0.405 mmol, 1.35 equiv.), N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ
2ꢀeneꢀ1ꢀcarboxamide (65.0 mg, 0.30 mmol, 1.0 equiv.), and a
quenching with saturated solution of iodine in dry dimethoxyꢀ
ethane, which was added until the coloration persisted. The
product was purified by column chromatography on Silica gel
eluting with hexane/EtOAc (mixture 3:1). The titled comꢀ
pound was obtained as a viscous colorless oil, Rf 0.45. Yield
68.2 mg (0.190 mmol, 63%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.41 – 7.19 (m, 5H), 3.56 – 3.46 (m, 1H), 3.50 (d, J
= 6.9 Hz, 1H), 3.43 – 3.33 (m, 1H), 3.33 – 3.23 (m, 2H), 1.45
– 1.35 (m, 4H), 1.16 (t, J = 7.1 Hz, 3H), 0.58 (t, J = 7.1 Hz,
3H); 13C NMR (126 MHz, CDCl3) δ 167.3, 140.4, 129.0 (+,
2C), 127.0 (+), 126.0 (+, 2C), 42.0 (ꢀ), 39.0 (ꢀ), 36.1, 26.5 (+),
18.1 (+), 12.6 (+), 12.6 (+), 7.2 (+); FTIR (KBr, cmꢀ1): 3057,
2970, 2931, 2872, 1633, 1599, 1496, 1444, 1425, 1379, 1315,
1296, 1278, 1263, 1234, 1219, 1149, 1122, 1103, 1080, 1066,
821, 761, 732; HRMS (TOF ES): Found 380.0474, calculated
for C15H20INONa (M+Na) 380.0487 (3.4 ppm).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1R*,2S*,3R*)-N,N-Dibenzyl-1-phenyl-2-propionyl-3-
vinylcyclopropane-1-carboxamide (23ce): This compound
was obtained via Typical procedure C employing vinylmagneꢀ
sium bromide (9e) (1.0 M in THF, 405 ꢁL 0.405 mmol, 1.35
equiv.),
N,Nꢀdibenzylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxamide (11c) (102 mg, 0.30 mmol, 1.0 equiv.), and
quenching with propionyl chloride (40.0 ꢁL, 42.0 mg, 0.45
mmol, 1.50 equiv.). The product was purified by column
chromatography on Silica gel eluting with hexane/EtOAc
(mixture 9:1). The titled compound was obtained as a viscous
colorless oil, Rf 0.19. Yield 66.1 mg (0.156 mmol, 52%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.50 – 7.41 (m, 2H),
7.34 – 7.20 (m, 6H), 7.17 – 7.03 (m, 5H), 6.57 – 6.46 (m, 1H),
6.48 – 6.44 (m, 2H), 5.32 (dd, J = 17.2, 1.8 Hz, 1H), 5.13 (dd,
J = 10.3, 1.8 Hz, 1H), 4.82 (d, J = 14.6 Hz, 1H), 4.52 (d, J =
15.5 Hz, 1H), 4.14 (d, J = 15.5 Hz, 1H), 3.95 (d, J = 14.6 Hz,
1H), 2.92 – 2.80 (m, 1H), 2.78 – 2.70 (m, 1H), 2.70 – 2.57 (m,
2H), 1.18 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
206.8, 167.8, 139.6, 136.8, 135.6, 132.8 (+), 129.2 (+, 2C),
129.0 (+, 2C), 128.4 (+, 2C), 128.4 (+, 2C), 127.9 (+, 2C),
127.8 (+), 127.5 (+, 2C), 127.4 (+), 127.4 (+), 117.6 (ꢀ), 50.2
(ꢀ), 46.7 (ꢀ), 45.7, 39.3 (+), 38.9 (ꢀ), 37.6 (+), 8.2 (+); FTIR
(KBr, cmꢀ1): 3061, 3028, 3003, 2978, 2935, 1707, 1643, 1633,
1602, 1494, 1450, 1417, 1361, 1329, 1315, 1267, 1234, 1193,
1178, 1122, 1080, 1039, 1030, 989, 945, 908, 806, 734, 700;
HRMS (TOF ES): Found 446.2100, calculated for
C29H29NO2Na (M+Na) 446.2096 (0.9 ppm).
(1R*,2S*,3S*)-N,N-Diethyl-1-phenyl-2-propionyl-3-
vinylcyclopropane-1-carboxamide (24ae): This compound
was obtained via Typical procedure C employing vinylmagneꢀ
sium bromide (9e) (1.0 M in THF, 405 ꢁL, 0.405 mmol, 1.35
equiv.), N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(11a) (65 mg, 0.30 mmol, 1.0 equiv.), quenching with saturatꢀ
ed solution of iodine in dry dimethoxyethane, which was addꢀ
ed until coloration persisted. The product was purified by colꢀ
umn chromatography on Silica gel eluting with hexane/EtOAc
(mixture 3:1). The titled compound was obtained as a viscous
yellowish oil, Rf 0.52. yield 56.0 mg (0.152 mmol, 51%), dr
>99:1. 1H NMR (500 MHz, CDCl3) δ 7.39 – 7.19 (m, 5H),
5.89 – 5.68 (m, 1H), 5.37 – 5.21 (m, 2H), 3.56 (d, J = 8.4 Hz,
1H), 3.52 – 3.41 (m, 1H), 3.36 – 3.24 (m, 2H), 3.21 (dq, J =
14.3, 7.1 Hz, 1H), 2.19 – 1.94 (m, 1H), 1.13 (t, J = 7.1 Hz,
3H), 0.54 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
166.7, 139.4, 138.7 (+), 129.1 (+, 2C), 127.4 (+), 126.0 (+,
2C), 117.5 (ꢀ), 42.0 (ꢀ), 39.2 (ꢀ), 38.8, 35.2 (+), 12.6 (+), 12.5
(+), 4.0 (+); FTIR (KBr, cmꢀ1): 3080, 3057, 3020, 2972, 2933,
2872, 1631, 1494, 1471, 1458, 1429, 1379, 1313, 1296, 1278,
1257, 1219, 1141, 1101, 1078, 979, 964, 904, 761, 700;
HRMS (TOF ES): Found 369.0601, calculated for C16H20INO
(M+) 369.0590 (3.0 ppm).
1-((1S*,2R*,3S*)-2,3-Diphenyl-2-(pyrrolidine-1-
carbonyl)cyclopropyl)propan-1-one (23dd): This compound
was obtained via Typical procedure C employing phenylꢀ
magnesium bromide (9d) (3.0 M in diethyl ether, 135 ꢁL,
0.405 mmol, 1.35 equiv.), (1ꢀphenylcyclopropꢀ2ꢀenꢀ1ꢀ
yl)(pyrrolidinꢀ1ꢀyl)methanone (11d) (64.0 mg, 0.30 mmol, 1.0
equiv.), and quenching with propionyl chloride (40.0 ꢁL, 42.0
mg, 0.45 mmol, 1.50 equiv.). The product was purified by
column chromatography on Silica gel eluting with hexꢀ
ane/EtOAc (mixture 3:1). The titled compound was obtained
(1R*,2R*,3S*)-N,N-Diethyl-2-((S*)-
o
as a colorless solid, mp 112.1ꢀ114.2 C, Rf 0.18. Yield 83.1
hydroxy(phenyl)methyl)-3-methyl-1-phenylcyclopropane-
1-carboxamide (25aa), Typical procedure D: Methylmagneꢀ
sium bromide (9a) (3.0 M in diethyl ether, 135 ꢁL, 0.405
mmol, 1.35 equiv.), was added dropwise to a suspension of
copper iodide (3.0 mg, 15.0 ꢁmol, 5.0 mol%) in anhydrous
freshly dried and distilled dimethoxyethane (1.0 mL), and the
mixture was stirred 0 oC for 5 min under nitrogen atmosꢀ
phere. N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
mg (0.239 mmol, 80%), dr: >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.54 – 7.14 (m, 10H), 3.41 – 3.26 (m, 2H), 3.12 (d, J
= 9.3 Hz, 1H), 3.12 – 3.05 (m, 1H), 2.85 – 2.74 (m, 1H), 2.68
– 2.53 (m, 2H), 2.36 (d, J = 9.3 Hz, 1H), 1.58 – 1.49 (m, 2H),
1.48 – 1.39 (m, 1H), 1.16 (t, J = 7.3 Hz, 3H), 1.06 – 0.95 (m,
1H); 13C NMR (126 MHz, CDCl3) δ 205.7, 166.4, 140.1,
134.1, 129.8 (+, 2C), 129.1 (+, 2C), 127.6 (+, 2C), 127.4 (+),
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The Journal of Organic Chemistry
0.31. Yield 110 mg (0.263 mmol, 88%), dr 93:7. 1H NMR
(11a) (65.0 mg, 0.30 mmol, 1.0 equiv.) dissolved in dry diꢀ
1
2
3
4
5
6
7
8
methoxyethane (1.0 mL) was then added slowly, and the stirꢀ
ring was continued for 15 min at 0 C, before freshly distilled
(400 MHz, CDCl3) δ 7.46 – 7.39 (m, 2H), 7.38 – 7.33 (m, 4H),
7.31 – 7.22 (m, 4H), 6.96 – 6.88 (m, 2H), 6.85 – 6.77 (m, 2H),
5.98 (s, 1H), 5.16 (d, J = 10.4 Hz, 1H), 3.58 (dq, J = 14.1, 7.2
Hz, 1H), 3.36 (dq, J = 14.4, 7.1 Hz, 1H), 3.30 – 3.21 (m, 1H),
3.19 (d, J = 10.0 Hz, 1H), 2.75 (dq, J = 14.1, 7.0 Hz, 1H), 1.65
(t, J = 10.2 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H), 0.33 (t, J = 7.1
Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 170.2 , 161.8 (d, J =
244.3 Hz), 141.0 , 139.1 (d, J = 3.5 Hz), 136.0 , 128.9 (d, J =
24.4 Hz, +, 2C), 128.4 (+, 2C) , 127.2 (d, J = 8.1 Hz, +, 2C),
127.1 (+, 2C) , 126.9 (+, 2C), 126.3 (+, 2C) , 114.8 (+) , 114.7
(+) , 68.1 (+) , 43.9 (+) , 41.9 (ꢀ) , 40.6 , 39.4 (ꢀ) , 32.2 (+) ,
11.9 (+), 11.8 (+); 19F NMR (376 MHz, CDCl3) δ ꢀ116.3 (s,
1F); FT IR (KBr, cmꢀ1): 3354, 2976, 2924, 1606, 1509, 1458,
1381, 1314, 1154, 1033, 767, 700; HRMS (TOF ES): Found
440.1987, calculated for C27H28FNO2Na (M+Na) 440.2002
(3.4 ppm).
o
benzaldehyde (48 mg, 46 ꢁL, 0.45 mmol, 1.50 equiv.) was
o
added. The mixture was stirred at 0 C for 30 min, then
warmed up to RT, and quenched with saturated aqueous amꢀ
monium chloride (1 mL). The resulting mixture was then
diluted with water (10 mL) and extracted with diethyl ether (3
x 5 mL). Combined organic layers were washed with brine,
dried, filtered, and evaporated. The product was purified by
column chromatography on Silica gel eluting with hexꢀ
ane/diethyl ether (mixture 2:1). The titled compound was obꢀ
9
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18
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43
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45
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49
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58
59
60
o
tained as colorless solid, mp 140.9ꢀ143.6 C, Rf 0.31. Yield
60.9 mg (0.180 mmol). 1H NMR (500 MHz, CDCl3) δ 7.48 –
7.42 (m, 2H), 7.35 – 7.27 (m, 4H), 7.26 – 7.16 (m, 4H), 5.81
(s, 1H), 4.78 (d, J = 10.3 Hz, 1H), 3.72 – 3.59 (m, 2H), 3.27 –
3.12 (m, 2H), 2.12 (dq, J = 9.6, 6.6 Hz, 1H), 1.42 (dd, J =
10.4, 9.6 Hz, 1H), 1.34 (d, J = 6.6 Hz, 3H), 1.18 (t, J = 7.1 Hz,
3H), 0.60 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
170.7, 143.8, 141.4, 128.9 (+, 2C), 128.5 (+, 2C), 127.3 (+),
126.7 (+), 126.3 (+, 2C), 126.2 (+, 2C), 70.8 (+), 42.2 (+),
41.9 (ꢀ), 39.2 (ꢀ), 38.6, 20.7 (+), 12.8 (+), 12.6 (+), 10.6 (+);
FT IR (KBr, cmꢀ1): 3358, 2972, 2935, 2875, 1608, 1495, 1422,
1380, 1347, 1318, 1252, 1155, 699; HRMS (TOF ES): Found
360.1949, calculated for C22H27NO2Na (M+Na) 360.1939 (2.8
ppm).
(1R*,2R*,3S*)-N,N-Diethyl-2-((R*)-1-hydroxy-2,2-
dimethylpropyl)-3-methyl-1-phenylcyclopropane-1-
carboxamide (27aa): This compound was obtained via typical
procedure D employing methylmagnesium bromide (9a)
(130.0 ꢁL, 3.0 M in THF, 0.390 mmol, 1.30 equiv.), N,Nꢀ
diethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0
mg, 0.30 mmol, 1.0 equiv.), and freshly distilled pivaldehyde
(38.8 mg, 48.9 ꢁL, 0.450 mmol, 1.50 equiv.). The product was
purified by column chromatography on silica gel eluting with
a mixture of hexane and diethyl ether (2:1). The titled comꢀ
pound was obtained as colorless solid, mp 138.1 – 139.4 oC, Rf
0.36. Yield 75.1 mg (0.237 mmol, 79%), dr >98:2. 1H NMR
(500 MHz, CDCl3) δ 7.34 – 7.29 (m, 2H), 7.27 – 7.19 (m, 3H),
5.79 (d, J = 2.3 Hz, 1H), 3.73 – 3.60 (m, 2H), 3.41 (dd, J =
10.5, 2.3 Hz, 1H), 3.18 – 3.06 (m, 2H), 2.10 (dq, J = 9.6, 6.6
Hz, 1H), 1.21 (d, J = 6.6 Hz, 3H), 1.20 – 1.16 (m, 1H), 1.15 (t,
J = 7.1 Hz, 3H), 0.99 (s, 9H), 0.52 (t, J = 7.1 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 171.0, 142.1, 128.9 (+, 2C), 126.5
(+), 126.2 (+, 2C), 74.8 (+), 41.8 (ꢀ), 39.1 (ꢀ), 38.0 (+), 36.9,
35.0, 26.3 (+, 3C), 21.3 (+), 12.5 (+), 12.4 (+), 11.1 (+); FT
IR (KBr, cmꢀ1): 3348, 3027, 2968, 2873, 1604, 1460, 1429,
1063, 1007, 702; HRMS (TOF ES): Found 340.2255, calcuꢀ
lated for C20H31NO2Na (M+Na) 340.2252 (0.9 ppm).
(1R*,2R*,3R*)-N,N-Diethyl-2-((S*)-
hydroxy(phenyl)methyl)-1,3-diphenylcyclopropane-1-
carboxamide (25ad): This compound was obtained via Typiꢀ
cal procedure C employing phenylmagnesium bromide (9d)
(3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.),
N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(11a)
(65.0 mg, 0.30 mmol, 1.0 equiv.), and quenching with freshly
distilled benzaldehyde (48 mg, 46 ꢁL, 0.45 mmol, 1.50
equiv.). The product was purified by column chromatography
on Silica gel eluting with hexane/diethyl ether (mixture 2:1).
The titled compound was obtained as colorless solid, mp
o
181.3ꢀ182.4 C, Rf 0.31. Yield 96.4 mg (0.241 mmol, 80%),
dr 96:4. 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.33 (m, 2H),
7.30 – 7.25 (m, 5H), 7.24 – 7.15 (m, 3H), 7.09 – 7.03 (m, 3H),
6.94 – 6.89 (m, 2H), 5.14 (d, J = 10.4 Hz, 1H), 3.51 (dq, J =
14.1, 7.1 Hz, 1H), 3.29 (dq, J = 14.3, 7.2 Hz, 1H), 3.19 (dq, J
= 14.1, 7.1 Hz, 1H), 3.13 (d, J = 10.1 Hz, 1H), 2.68 (dq, J =
14.2, 7.1 Hz, 1H), 1.64 (t, J = 10.3 Hz, 1H), 1.19 (s, 1H,
broad), 1.11 (t, J = 7.1 Hz, 3H), 0.26 (t, J = 7.1 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 170.3, 143.4, 141.2, 136.1, 128.9
(+, 2C), 128.8 (+, 2C), 128.3 (+, 2C), 128.0 (+, 2C), 127.0 (+),
126.8 (+), 126.8 (+), 126.3 (+, 2C), 125.6 (+, 2C), 68.5 (+),
44.1 (+), 41.9 (ꢀ), 40.6 , 39.3 (ꢀ), 32.4 (+), 11.9 (+), 11.9 (+);
FT IR (KBr, cmꢀ1): 3355. 3060, 3029, 2976, 2935, 1605, 1497,
1429, 1381, 1278, 1195, 1151, 741; HRMS (TOF ES): Found
422.2098, calculated for C27H29NO2Na (M+Na) 422.2096 (0.5
ppm).
(1R*,2R*,3R*)-N,N-Diethyl-2-((S*)-1-hydroxy-2,2-
dimethylpropyl)-1,3-diphenylcyclopropane-1-carboxamide
(27ad): This compound was obtained via Typical procedure C
employing phenylmagnesium bromide (9d) (3.0 M in diethyl
ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.), N,Nꢀdiethylꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (65.0 mg, 0.30
mmol, 1.0 equiv.), and quenching with freshly distilled pivalic
aldehyde (39.0 mg, 50.0 ꢁL, 0.45 mmol, 1.50 equiv.). The
product was purified by column chromatography on Silica gel
eluting with hexane/diethyl ether (mixture 2:1). The titled
compound was obtained as colorless solid, mp 196.9ꢀ198.0 oC,
Rf 0.38. Yield 94.2 mg (0.248 mmol, 83%), dr >99:1. 1H
NMR (500 MHz, CDCl3) δ 7.43 – 7.39 (m, 2H), 7.37 – 7.31
(m, 2H), 7.29 – 7.19 (m, 6H), 3.85 (d, J = 10.7 Hz, 1H), 3.52
(dq, J = 14.1, 7.2 Hz, 1H), 3.25 (dq, J = 14.3, 7.2 Hz, 1H),
3.19 – 3.10 (m, 1H), 3.13 (d, J = 9.9 Hz, 1H), 2.61 (dq, J =
14.2, 7.1 Hz, 1H), 1.65 (s, 1H), 1.53 (t, J = 10.4 Hz, 1H), 1.10
(t, J = 7.1 Hz, 3H), 0.73 (s, 9H), 0.25 (t, J = 7.1 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 170.5, 141.9, 137.1, 129.1 (+, 2C),
129.0 (+, 2C), 128.2 (+, 2C), 126.9 (+), 126.5 (+), 126.5 (+,
2C), 72.7 (+), 41.8 (ꢀ), 39.3 (ꢀ), 39.1 (+), 39.0 , 35.3, 33.5 (+),
26.2 (+, 3C), 12.0 (+), 11.9 (+); FT IR (KBr, cmꢀ1): 3363,
(1R*,2R*,3R*)-N,N-Diethyl-2-((S*)-(4-fluorophenyl)-
(hydroxy)methyl)-1,3-diphenylcyclopropane-1-
carboxamide (26ad): This compound was obtained via Typiꢀ
cal procedure C employing phenylmagnesium bromide (9d)
(3.0 M in diethyl ether, 135 ꢁL, 0.405 mmol, 1.35 equiv.),
N,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(11a)
(65.0 mg, 0.30 mmol, 1.0 equiv.), and quenching with 4ꢀ
fluorobenzaldehyde (58.0 mg, 50.0 ꢁL, 0.45 mmol, 1.50
equiv.). The titled compound was obtained as colorless oil, Rf
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2964, 2648, 1595, 1463, 1442, 1433, 1007, 765, 699; HRMS the mixture was stirred for 15 minutes. The reaction was then
1
2
3
4
5
6
7
8
(TOF ES): Found 402.2411, calculated for C25H33NO2Na
(M+Na) 402.2409 (0.5 ppm).
filtered through a silica gel plug eluting with ethyl acetate,
evaporated, and further purified by silica gel column chromaꢀ
tography using 6:1 hexane/ethyl acetate mixture as a mobile
phase. The titled compound was obtained as colorless oil, Rf
0.37. Yield 43.4 mg (0.177 mmol, 89%). 1H NMR (500
MHz, CDCl3) δ 7.39 – 7.32 (m, 2H), 7.30 – 7.23 (m, 2H), 7.22
– 7.17 (m, 1H), 3.86 (s, 1H), 2.32 (d, J = 8.2 Hz, 1H), 1.76
(dq, J = 8.2, 6.5 Hz, 1H), 1.21 (d, J = 6.5 Hz, 3H), 0.98 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 174.5, 135.5, 128.7 (+,
2C), 127.8 (+, 2C), 127.5 (+), 83.4 (+), 37.5, 34.6, 31.5 (+),
25.2 (+, 3C), 25.0 (+), 8.4 (+); FTIR (KBr, cmꢀ1): 3060, 2962,
2907, 2873, 1759, 1500, 1335, 1112, 994, 908, 754, 697;
HRMS (TOF ES): Found 267.1358, calculated for
C16H20O2Na (M+Na) 267.1361 (1.1 ppm).
(1S*,2R*,3S*)-N,N-Diethyl-2-((S*)-1-hydroxy-2,2-
dimethylpropyl)-1-phenyl-3-((trimethylsilyl)-
methyl)cyclopropane-1-carboxamide (27ag): This comꢀ
pound was obtained via Typical procedure C employing (triꢀ
methylsilyl)methylmagnesium chloride (9g) (1.30 M in THF,
450 ꢁL, 0.60 mmol, 1.30 equiv.), N,Nꢀdiethylꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11a) (98.0 mg, 0.45
mmol, 1.00 equiv.), and quenching with freshly distilled pivalꢀ
ic aldehyde (59.0 mg, 75.0 ꢁL, 0.68 mmol, 1.50 equiv.). The
product was purified by column chromatography on Silica gel
eluting with hexane/diethyl ether (mixture 2:1). The titled
compound was obtained as colorless oil, Rf 0.45. Yield 138
mg (0.354 mmol, 79%), dr >99:1. 1H NMR (500 MHz,
CDCl3) δ 7.32 – 7.27 (m, 2H), 7.24 – 7.16 (m, 3H), 3.61 (dq, J
= 14.0, 7.1 Hz, 1H), 3.57 – 3.48 (m, 1H), 3.48 (d, J = 10.0 Hz,
1H) , 3.14 (dq, J = 14.0, 7.0 Hz, 1H), 2.97 (dq, J = 14.0, 7.0
Hz, 1H), 2.02 – 1.92 (m, 1H), 1.14 – 1.09 (m, 1H), 1.12 (t, J =
7.1 Hz, 3H), 0.96 (s, 9H), 0.88 (dd, J = 15.7, 5.2 Hz, 1H), 0.43
(t, J = 7.1 Hz, 3H), 0.43 – 0.38 (m, 1H), 0.12 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 171.2, 142.4, 129.0 (+, 2C), 126.5
(+), 126.4 (+, 2C), 74.6 (+), 42.0 (ꢀ), 39.3 (ꢀ), 38.6 (+), 38.5,
35.5, 26.5 (+, 3C), 20.9 (+), 12.5 (+), 12.3 (+), 10.2 (ꢀ), ꢀ1.1
(+, 3C); FT IR (KBr, cmꢀ1): 3365, 2951, 2901, 1614, 1479,
1462, 1445, 1249, 1184, 1064, 846, 698; HRMS (TOF ES):
Found 412.2644, calculated for C23H39NO2SiNa (M+Na)
412.2648 (1.0 ppm).
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(1S*,2S*)-2-Butyl-N,N-diethyl-2-methyl-1-
phenylcyclopropane-1-carboxamide
(41aa)
and
(1S*,2S*,3S*)-2-butyl-N,N-diethyl-3-methyl-1-
phenylcyclopropane-1-carboxamide (42aa):
These compounds were obtained via typical procedure A
employing methylmagnesium bromide (130.0 ꢁL, 3.0 M in
THF, 0.390 mmol, 1.30 equiv.) and 2ꢀbutylꢀN,Nꢀdiethylꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (38a) (82.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
matography on silica gel eluting with a mixture of hexane and
ethyl acetate (6:1). The mixture of inseparable regioisomeric
products titled compound was obtained as a colorless oil, Rf
0.29. Yield 77.3 mg (0.269 mmol, 90%), 41aa:42aa ratio
88:12, dr >98:2 (for both regioisomers). 1H NMR (500 MHz,
CDCl3) Mix of Regioisomers: δ [7.48 – 7.39 (m), Σ2H], [7.30
– 7.23 (m), Σ2H], [7.21 – 7.15 (m), Σ1H], [3.68 – 3.49 (m) &
3.44 – 3.28 (m) & 3.18 (dq, J = 14.0, 7.1 Hz) & 3.07 (dq, J =
13.9, 7.0 Hz) & 2.96 (dq, J = 14.0, 7.0 Hz), Σ4H], [1.62 – 1.54
(m) & 1.36 – 0.97 (m), Σ8H], [1.29 (d, J = 5.0 Hz) & 1.22 (s),
Σ3H], [1.01 (t, J = 7.1 Hz), Σ3H], [0.83 (t, J = 7.1 Hz) & 0.75
(t, J = 7.1 Hz), Σ3H], [0.71 (t, J = 7.4 Hz) & 0.33 (t, J = 7.0
Hz), Σ3H]; 13C NMR (126 MHz, CDCl3) Mix of Regioisoꢀ
mers: δ [171.0 & 170.8], [138.6 & 138.3], [129.4 (+) & 129.3
(+), Σ2C], [128.1 (+) & 128.0 (+), Σ2C], [126.4 (+) & 126.2
(+)], [41.4 (ꢀ) & 41.0 (ꢀ)], [40.8 & 39.8], [39.4 (ꢀ) & 39.1 (ꢀ)],
[35.2 (ꢀ) & 31.2 (+) & 31.1 (ꢀ) & 28.5 (ꢀ) & 28.4 & 28.3 (ꢀ) &
24.0 (ꢀ) & 22.8 (ꢀ) & 22.3 (ꢀ) & 22.0 (+) & 21.9 (+) & 14.2 (+)
& 14.0 (+) & 13.9 (+) & 13.5 (+) & 12.5 (+) & 12.4 (+) &
12.2 (+), Σ9C]; FTIR (KBr, cmꢀ1): 3047, 2958, 2932, 2871,
1632, 1457, 1421, 1269, 1105, 729, 701; HRMS (TOF ES):
Found 310.2143, calculated for C19H29NONa (M+Na)
310.2147 (1.3 ppm).
(1R*,2R*,3S*)-2-((R*)-1-Hydroxy-2,2-dimethylpropyl)-
N-methoxy-N,3-dimethyl-1-phenylcyclopropane-1-
carboxamide (27ha): This compound was obtained via typiꢀ
cal procedure D using methylmagnesium bromide (9a) (260
ꢁL, 3.0 M in THF, 0.780 mmol, 1.30 equiv.), NꢀmethoxyꢀNꢀ
methylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (11h) (122.0
mg, 0.60 mmol, 1.0 equiv.), and freshly distilled pivaldehyde
(77.6 mg, 98.0 ꢁL, 0.90 mmol, 1.50 equiv.). The product was
purified by column chromatography on silica gel eluting with
a mixture hexane and diethyl ether (2:1). The titled compound
was obtained as colorless oil, Rf 0.30. Yield 151 mg (0.494
1
mmol, 82%), dr >98:2. 1H NMR (500 MHz, CDCl3): H
NMR (500 MHz, C6D6) δ 7.25 – 7.19 (m, 2H), 7.10 – 7.03
(m, 2H), 7.01 – 6.95 (m, 1H), 5.36 (s, 1H), 3.61 (d, J = 10.4
Hz, 1H), 2.77 (s, 3H), 2.75 (s, 3H), 1.93 – 1.81 (m, 1H), 1.30
(t, J = 9.9 Hz, 1H), 1.15 (d, J = 6.7 Hz, 3H), 1.11 (s, 9H); 13C
NMR (126 MHz, C6D6) δ 172.8, 142.7, 128.8 (+, 2C), 127.5
(+), 126.6 (+, 2C), 74.9 (+), 59.9 (+), 38.0 (+), 37.7, 35.4, 33.0
(+), 26.6 (+, 3C), 22.2 (+), 10.9 (+); FT IR (KBr, cmꢀ1): 3416,
3061, 2953, 2905, 1631, 1460, 1380, 1178, 1007, 699, 611;
HRMS (TOF ES): Found 328.1885, calculated for
C18H27NO3Na (M+Na) 328.1889 (1.2 ppm).
(1R*,2S*,3R*)-2-Butyl-N,N-diethyl-1,3-
diphenylcyclopropane-1-carboxamide
(42ad)
and
(1R*,2S*)-2-butyl-N,N-diethyl-1,2-diphenylcyclopropane-
1-carboxamide (41ad): These compounds were obtained via
typical procedure A using phenylmagnesium bromide (130.0
ꢁL, 3.0 M in diethyl ether, 0.390 mmol, 1.30 equiv.) and 2ꢀ
butylꢀN,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(1R*,4S*,5S*,6R*)-4-(tert-Butyl)-6-methyl-1-phenyl-3-
oxabicyclo[3.1.0]hexan-2-one (28):
1
pꢀToluenesulfonic acid monohydrate (47.0 mg, 0.25 mmol,
1.2 equiv.) was added to a solution of (1R*,2R*,3S*)ꢀ2ꢀ((R*)ꢀ
1ꢀhydroxyꢀ2,2ꢀdimethylpropyl)ꢀNꢀmethoxyꢀN,3ꢀdimethylꢀ1ꢀ
phenylcyclopropaneꢀ1ꢀcarboxamide (27ha) (61.0 mg, 0.20
mmol, 1.0 equiv.) in benzene (5 mL) and the mixture was
stirred for 10 minutes. The reaction was then warmed to 50 oC
and stirred for 1 h. After cooling to room temperature, potasꢀ
sium carbonate (35 mg, 0.25 mmol, 1.2 equiv.) was added and
(38a) (82.0 mg, 0.30 mmol, 1.0 equiv.). H NMR analysis of
the crude mixture showed 42ad:41ad ratio 70:30. The isoꢀ
mers were separated by column chromatography on silica gel
eluting with a mixture of hexane and ethyl acetate (6:1). The
major regioisomer 42ad was isolated as a colorless oil, Rf
0.40. Yield 66.6 mg (0.190 mmol, 64%), dr >98:2. 1H NMR
(500 MHz, CDCl3) δ 7.45 – 7.39 (m, 2H), 7.39 – 7.32 (m, 2H),
7.29 – 7.26 (m, 3H), 7.26 – 7.23 (m, 2H), 7.21 – 7.17 (m, 1H),
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(ꢀ), 32.4 (+), 31.5 (+), 31.0 (ꢀ), 28.2 (ꢀ), 22.4 (ꢀ), 14.1 (+), 12.4
3.49 – 3.25 (m, 2H), 2.79 (d, J = 6.8 Hz, 1H), 2.73 (dq, J =
1
2
3
4
5
6
7
8
14.0, 7.1 Hz, 1H), 2.54 – 2.46 (m, 1H), 2.40 (dq, J = 14.0, 7.0
Hz, 1H), 1.41 – 1.14 (m, 5H), 0.94 – 0.81 (m, 1H), 0.77 (t, J =
7.3 Hz, 3H), 0.65 (t, J = 7.1 Hz, 3H), 0.13 (t, J = 7.1 Hz, 3H);
13C NMR (126 MHz, CDCl3) δ 169.5, 137.9, 137.9, 128.7 (+,
2C), 128.5 (+, 2C), 128.2 (+, 2C), 127.5 (+, 2C), 126.8 (+),
126.3 (+), 45.9, 40.8 (ꢀ), 39.1 (ꢀ), 33.6 (+), 31.0 (ꢀ), 30.2 (+),
28.7 (ꢀ), 22.5 (ꢀ), 14.1 (+), 11.9 (+), 11.7 (+); FT IR (KBr, cmꢀ
1): 3058, 3023, 2957, 2932, 2870, 1631, 1445, 1379, 1274,
1080, 700; HRMS (TOF ES): Found 372.2321, calculated for
C24H31NONa (M+Na) 372.2303 (4.8 ppm). The minor regioiꢀ
somer 41ad was isolated as a colorless oil, Rf 0.26. Yield 28.5
mg (0.082 mmol, 27%), dr >98:2. 1H NMR (500 MHz,
CDCl3) δ 7.62 – 7.53 (m, 2H), 7.41 – 7.37 (m, 2H), 7.36 –
7.31 (m, 2H), 7.30 – 7.26 (m, 2H), 7.25 – 7.21 (m, 1H), 7.19 –
7.14 (m, 1H), 3.73 (dq, J = 14.2, 7.1 Hz, 1H), 3.11 – 2.90 (m,
2H), 2.79 (dq, J = 13.8, 7.0 Hz, 1H), 2.32 (d, J = 5.3 Hz, 1H),
2.30 – 2.21 (m, 1H), 1.30 (d, J = 5.3 Hz, 1H), 1.20 – 1.03 (m,
4H), 1.02 – 0.93 (m, 1H), 0.71 (t, J = 7.0 Hz, 3H), 0.65 (t, J =
7.0 Hz, 3H), 0.46 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 169.4, 140.1, 139.1, 130.4 (+, 2C), 128.9 (+, 2C),
128.4 (+, 2C), 127.8 (+, 2C), 126.8 (+), 126.2 (+), 42.9, 41.7 (ꢀ
), 39.3 (ꢀ), 37.5, 36.8 (ꢀ), 29.4 (ꢀ), 22.8 (ꢀ), 22.6 (ꢀ), 14.2 (+),
13.4 (+), 11.8 (+). HRMS (TOF ES): Found 372.2317, calcuꢀ
lated for C24H31NONa (M+Na) 372.2303 (3.8 ppm).
(+), 12.4 (+); HRMS (TOF ES): Found 322.2152, calculated
for C20H29NONa (M+Na) 322.2147 (1.6 ppm).
(1R*,2S*,3S*)-2-Butyl-N,N-diethyl-1-phenyl-3-
((trimethylsilyl)methyl)cyclopropane-1-carboxamide
(42ag). This compound was obtained via typical procedure A
using (trimethylsilyl)methylmagnesium chloride (300 ꢁL, 1.3
M in THF, 0.390 mmol, 1.3 equiv.) and 2ꢀbutylꢀN,Nꢀdiethylꢀ
1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (38a) (82.0 mg, 0.30
1
9
mmol, 1.0 equiv.). H NMR analysis of the crude mixture
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
showed 42ag:41ag ratio 75:25. The major regioisomers was
isolated by column chromatography on silica gel eluting with
a mixture of hexane and ethyl acetate (6:1). The titled comꢀ
pound was obtained as a pale yellow oil, Rf 0.46. Yield 80.7
mg, yield (0.224 mmol, 75%), dr >98:2. 1H NMR (500 MHz,
CDCl3) δ 7.28 – 7.15 (m, 5H), 3.62 (dq, J = 14.4, 7.1 Hz, 1H),
3.49 (dq, J = 13.8, 7.0 Hz, 1H), 3.13 (dq, J = 13.9, 7.0 Hz,
1H), 2.94 (dq, J = 14.0, 7.0 Hz, 1H), 1.64 – 1.48 (m, 2H), 1.31
– 1.10 (m, 4H), 1.07 (t, J = 7.1 Hz, 3H), 1.05 – 0.97 (m, 1H),
0.87 – 0.76 (m, 2H), 0.69 (t, J = 7.0 Hz, 3H), 0.31 (t, J = 7.0
Hz, 3H), 0.17 (dd, J = 14.4, 11.9 Hz, 1H), 0.08 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 171.5, 138.8, 128.9 (+, 2C)), 128.2
(+, 2C), 126.3 (+), 41.4 (ꢀ), 41.3, 39.6 (ꢀ), 31.6 (+), 31.0 (ꢀ),
28.7 (ꢀ), 23.6 (+), 22.6 (ꢀ), 16.3 (ꢀ), 14.0 (+), 12.6 (+), 12.3 (+),
ꢀ1.2 (+, 3C); FT IR (KBr, cmꢀ1): 3057, 2955, 2932, 2872,
1633, 1457, 1423, 1271, 1247, 860, 838, 758, 701; HRMS
(TOF ES): Found 382.2552, calculated for C22H37NOSiNa
(M+Na) 382.2542 (2.6 ppm).
(1S*,2S*)-2-Butyl-N,N-diethyl-1-phenyl-2-
vinylcyclopropane-1-carboxamide
(41ae)
and
(1R*,2S*,3S*)-2-butyl-N,N-diethyl-1-phenyl-3-
vinylcyclopropane-1-carboxamide (42ae): These compounds
were obtained via typical procedure A using vinylmagnesium
bromide (390 ꢁL, 1.0 M in THF, 0.390 mmol, 1.30 equiv.)
(1S*,2S*,3R*)-N,N-Diethyl-2-methyl-1,3-
diphenylcyclopropane-1-carboxamide
(42ba)
and
and
2ꢀbutylꢀN,Nꢀdiethylꢀ1ꢀphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
(1R*,2R*)-N,N-diethyl-2-methyl-1,2-diphenyl-
carboxamide (38a) (82.0 mg, 0.30 mmol, 1.0 equiv.). 1H NMR
analysis of the crude mixture showed 41ae:42ae ratio 81:19.
The isomers were separated by column chromatography on
silica gel eluting with a mixture of hexane and ethyl acetate
(6:1). The major regioisomer 41ae was isolated as a colorꢀ
less oil, Rf 0.30. Yield 63.7 mg (0.213 mmol, 71%), dr >98:2.
1H NMR (500 MHz, CDCl3) δ 7.49 – 7.43 (m, 2H), 7.32 –
7.27 (m, 2H), 7.24 – 7.19 (m, 1H), 5.94 (dd, J = 17.2, 10.5 Hz,
1H), 5.05 (dd, J = 10.5, 1.4 Hz, 1H), 4.98 (dd, J = 17.2, 1.4
Hz, 1H), 3.56 (dq, J = 14.2, 7.1 Hz, 1H), 3.36 (dq, J = 14.2,
7.1 Hz, 1H), 3.27 (dq, J = 14.1, 7.1 Hz, 1H), 3.17 (dq, J =
13.9, 7.1 Hz, 1H), 1.62 (d, J = 5.3 Hz, 1H), 1.61 – 1.51 (m,
1H), 1.36 (d, J = 5.2 Hz, 1H), 1.34 – 1.28 (m, 1H), 1.24 – 1.02
(m, 3H), 0.97 (t, J = 7.1 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H), 0.81
– 0.76 (m, 1H), 0.74 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 170.1, 141.1 (+), 137.8, 129.7 (+, 2C), 128.4 (+,
2C), 126.9 (+), 113.1 (ꢀ), 42.3, 41.6 (ꢀ), 39.2 (ꢀ), 35.4, 32.8 (ꢀ),
29.0 (ꢀ), 22.8 (ꢀ), 21.7 (ꢀ), 14.1 (+), 13.7 (+), 12.6 (+); FT IR
(KBr, cmꢀ1): 3052, 2958, 2932, 2871, 1633, 1458, 1424, 1275,
1100, 902, 701; HRMS (TOF ES): Found 322.2157, calculatꢀ
ed for C20H29NONa (M+Na) 322.2147 (3.1 ppm). The minor
regioisomer 42ae was isolated as a colorless oil, Rf 0.40. Yield
15.0 mg (0.050 mmol, 17%), dr >98:2. 1H NMR (500 MHz,
CDCl3) δ 7.32 – 7.26 (m, 4H), 7.24 – 7.19 (m, 1H), 5.47 –
5.35 (m, 1H), 5.26 (dd, J = 17.0, 1.8 Hz, 1H), 5.01 (dd, J =
10.1, 1.8 Hz, 1H), 3.61 – 3.44 (m, 2H), 3.06 (dq, J = 13.8, 7.0
Hz, 1H), 2.89 (dq, J = 14.1, 7.0 Hz, 1H), 2.26 (dd, J = 9.2, 6.0
Hz, 1H), 2.05 – 1.88 (m, 1H), 1.35 – 1.07 (m, 6H), 1.04 (t, J =
7.1 Hz, 3H), 0.75 (t, J = 7.2 Hz, 3H), 0.34 (t, J = 7.0 Hz, 3H);
13C NMR (126 MHz, CDCl3) δ 170.5, 137.6, 137.0 (+), 128.6
(+, 2C), 128.4 (+, 2C), 126.7 (+), 115.2 (ꢀ), 42.7, 41.1 (ꢀ), 39.6
cyclopropane-1-carboxamide (41ba): These compounds
were obtained via typical procedure A employing methylꢀ
magnesium bromide (130.0 ꢁL, 3.0 M in THF, 0.390 mmol,
1.30 equiv.) and N,Nꢀdiethylꢀ1,2ꢀdiphenylcyclopropꢀ2ꢀeneꢀ1ꢀ
carboxamide (38b) (88.0 mg, 0.30 mmol, 1.0 equiv.). The
product was purified by column chromatography on silica gel
eluting with a mixture of hexane:ethyl acetate (6:1). A mixꢀ
ture of inseparable regioisomers was obtained as a colorless
amorphous solid, Rf 0.26. Yield 85.3 mg (0.277 mmol,
92%), 42ba:41ba ratio 91:9, dr >98:2. 1H NMR (500 MHz,
CDCl3): Mixture of regioisomers: δ [7.11 – 7.07 (m), Σ4H],
[7.03 – 6.98 (m), Σ3H], [6.98 – 6.92 (m), Σ3H], [3.70 (dq, J =
14.3, 7.1 Hz) & 3.58 (dq, J = 13.9, 7.1 Hz) & 3.41 – 3.34 (m)
& 3.13 (dq, J = 13.5, 7.0 Hz) & 3.07 (dq, J = 14.2, 7.2 Hz),
Σ4H], [3.01 (d, J = 6.7 Hz) & 2.08 (d, J = 5.4 Hz), Σ1H], [2.40
(dt, J = 6.3 Hz) & 1.50 (d, J = 5.4 Hz), Σ1H], [1.61 (s) & 1.31
(d, J = 6.2 Hz), Σ3H], [1.11 (t, J = 7.1 Hz), Σ3H], [0.84 (t, J =
7.1 Hz) & 0.40 (t, J = 7.0 Hz, 1H), Σ3H]; 13C NMR (126
MHz, CDCl3) δ 170.3, 137.6, 137.1, 128.9 (+, 2C), 128.6 (+,
2C), 128.1 (+, 2C), 127.6 (+, 2C), 126.4 (+), 125.7 (+), 44.7,
41.4 (ꢀ), 39.7 (ꢀ), 36.6 (+), 21.3 (+), 14.4 (+), 12.6 (+), 12.5
(+); FT IR (KBr, cmꢀ1): 3041, 2967, 1629, 1458, 1425, 1276,
1140, 697; HRMS (TOF ES): Found 330.1840, calculated for
C21H25NONa (M+Na) 330.1834 (1.8 ppm).
(2R*,3R*)-N,N-Diethyl-1,2,3-triphenylcyclopropane-1-
carboxamide (42bd): This compound was obtained via typiꢀ
cal procedure A employing phenylmagnesium bromide (130.0
ꢁL, 3.0 M in diethyl ether, 0.390 mmol, 1.30 equiv.) and N,Nꢀ
diethylꢀ1,2ꢀdiphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(38b)
(88.0 mg, 0.30 mmol, 1.0 equiv.). The product was purified by
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column chromatography on silica gel eluting with a mixture of
IR (KBr, cmꢀ1): 3056, 2956, 2902, 1622, 1443, 1426, 1250,
858, 832, 696; HRMS (TOF ES): Found 402.2226, calculated
for C24H33NOSiNa (M+Na) 402.2229 (0.7 ppm).
1
2
3
4
5
6
7
8
hexane and ethyl acetate (6:1). The titled compound was obꢀ
tained as a colorless solid, mp 174.3 – 175.6 oC, Rf 0.27. Yield
99.2 mg (0.268 mmol, 89%), 42bd:41bd ratio >98:2, dr
>98:2. 1H NMR (500 MHz, CDCl3) δ 7.41 – 7.36 (m, 2H),
7.33 – 7.29 (m, 2H), 7.26 – 7.20 (m, 3H), 7.17 – 7.12 (m, 2H),
7.11 – 7.03 (m, 5H), 7.02 – 6.97 (m, 1H), 3.90 (d, J = 7.3 Hz,
1H), 3.55 (d, J = 7.3 Hz, 1H), 3.51 – 3.31 (m, 2H), 2.77 (dq, J
= 13.9, 7.0 Hz, 1H), 2.48 (dq, J = 14.1, 7.0 Hz, 1H), 0.69 (t, J
= 7.1 Hz, 3H), 0.17 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 168.7, 136.9, 136.8, 136.6, 128.8 (+, 2C), 128.6 (+,
2C), 128.4 (+, 2C), 128.3 (+, 2C), 127.8 (+, 2C), 127.7 (+,
2C), 126.8 (+), 126.7 (+), 126.1 (+), 48.6, 41.0 (ꢀ), 39.2 (ꢀ),
35.2 (+), 32.5 (+), 12.0 (+), 11.8 (+); FT IR (KBr, cmꢀ1):
3046, 3029, 2974, 2934, 1624, 1446, 1277, 1078, 774, 750,
697; HRMS (TOF ES): Found 392.1982, calculated for
C26H27NONa (M+Na) 392.1990 (2.0 ppm).
(1S*,2S*,3R*)-N,N-Diethyl-2-methyl-1-phenyl-3-(p-
tolyl)cyclopropane-1-carboxamide (42ca) and (1R*,2R*)-
N,N-diethyl-2-methyl-1-phenyl-2-(p-tolyl)cyclopropane-1-
carboxamide (41ca):
These compounds were obtained via typical procedure A
employing methylmagnesium bromide (130 ꢁL, 3.0 M in
THF, 0.390 mmol, 1.30 equiv.) and N,N-diethylꢀ1ꢀphenylꢀ2ꢀ
(pꢀtolyl)cyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (38c) (92.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column
chromatography on silica eluting with a mixture of hexane and
ethyl acetate (6:1). A mixture of inseparable regioisomers was
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
obtained as a colorless solid, mp 115.7 – 118.3 C, Rf 0.26.
Yield 93.5 mg (0.291 mmol, 97 %), 42ca:41ca ratio 86:14, dr
>98:2. 1H NMR (500 MHz, CDCl3): δ [7.13 – 7.07 (m, Σ4H)],
[7.05 – 6.99 (m, Σ1H)], [6.87 – 6.79 (m, Σ4H)], [3.70 (dq, J =
14.3, 7.1 Hz) & 3.58 (dq, J = 14.0, 7.1 Hz) & 3.42 – 3.33 (m)
& 3.12 (dq, J = 14.0, 7.0 Hz) & 3.05 (dq, J = 14.0, 7.0 Hz),
Σ4H], [2.96 (d, J = 6.7 Hz) & 2.39 – 2.32 (m) & 2.02 (d, J =
5.7 Hz), Σ2H], [2.21 (s) & 2.14 (s), Σ3H], [1.58 (s) & 1.30 (d,
J = 6.2 Hz), Σ3H], [1.11 (t, J = 7.1 Hz), Σ3H], [0.82 (t, J = 7.0
Hz) & 0.40 (t, J = 7.0 Hz), Σ3H]; 13C NMR (126 MHz,
CDCl3) δ [170.6 & 170.3, Σ1C], [139.2 & 138.1 & 137.2 &
135.5 & 135.0 & 134.4, Σ3C], [128.9 (+) & 128.7 (+) & 128.6
(+) & 128.4 (+) & 128.4 (+) & 128.3 (+) & 128.1 (+) & 127.8
(+), Σ8C], [126.3 (+) & 126.0 (+), Σ1C], [57.1 & 44.6, Σ1C],
[41.6 (ꢀ) & 41.3 (ꢀ) & 39.7 (ꢀ) & 39.3 (ꢀ), Σ2C], [36.3 (+) &
26.8, Σ1C], [24.1 (ꢀ) & 21.4 (+), Σ1C], [21.1 (+) & 21.0 (+),
Σ1C], [14.5 (+) & 14.4 (+), Σ1C], [12.5 (+) & 12.5 (+) & 12.5
(+) & 12.5 (+), Σ2C]; FT IR (KBr, cmꢀ1): 3062, 2968, 2932,
2871, 1632, 1457, 1425, 1276, 1219, 1140, 811, 700; HRMS
(TOF ES): Found 344.1989, calculated for C22H27NONa
(M+Na) 344.1990 (0.3 ppm).
(1S*,2R*,3S*)-N,N-Diethyl-1,2-diphenyl-3-
vinylcyclopropane-1-carboxamide (42be): This compound
was obtained via typical procedure A using vinylmagnesium
bromide (390.0 ꢁL, 1.0 M in THF, 0.390 mmol, 1.30 equiv.)
and N,Nꢀdiethylꢀ1,2ꢀdiphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide
(38b) (88.0 mg, 0.30 mmol, 1.0 equiv.). The product was puriꢀ
fied by column chromatography on silica gel eluting with a
mixture of hexane and ethyl acetate (6:1). The titled comꢀ
o
pound was obtained as a colorless solid, mp 101.3 – 101.9 C,
Rf 0.30. Yield 80.4 mg, (0.252 mmol, 84%), 42be:41be ratio
98:2, dr >98:2. 1H NMR (500 MHz, CDCl3) δ 7.16 – 7.09 (m,
4H), 7.06 – 7.00 (m, 3H), 7.00 – 6.94 (m, 3H), 5.59 (ddd, J =
17.0, 10.1, 9.0 Hz, 1H), 5.43 (dd, J = 17.0, 1.5 Hz, 1H), 5.15
(dd, J = 10.2, 1.5 Hz, 1H), 3.63 – 3.50 (m, 2H), 3.37 (d, J =
6.5 Hz, 1H), 3.12 (dq, J = 13.9, 7.0 Hz, 1H), 3.03 (dd, J = 8.9,
6.5 Hz, 1H), 3.01 – 2.94 (m, 1H), 1.09 (t, J = 7.1 Hz, 3H),
0.41 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
169.7, 136.6, 136.2, 135.9 (+), 128.6 (+, 2C), 128.6 (+, 2C),
128.3 (+, 2C), 127.7 (+, 2C), 126.7 (+), 126.0 (+), 116.4 (ꢀ),
45.6, 41.3 (ꢀ), 39.7 (ꢀ), 36.3 (+), 31.5 (+), 12.5 (+), 12.4 (+);
FT IR (KBr, cmꢀ1): 3059, 3027, 2976, 2934, 1630, 1445, 1428,
1276, 1134, 908, 753, 697; HRMS (TOF ES): Found
342.1820, calculated for C22H25NONa (M+Na) 342.1834 (4.1
ppm).
(1S*,2R*,3S*)-N,N-Diethyl-2-(4-fluorophenyl)-3-methyl-
1-phenylcyclopropane-1-carboxamide
(42da)
and
(1R*,2R*)-N,N-diethyl-2-(4-fluorophenyl)-2-methyl-1-
phenylcyclopropane-1-carboxamide (41da): These comꢀ
pounds were obtained via typical procedure A using methylꢀ
magnesium bromide (130 ꢁL, 3.0 M in THF, 0.390 mmol,
(1R*,2R*,3S*)-N,N-Diethyl-1,2-diphenyl-3-
1.30
equiv.)
and
N,Nꢀdiethylꢀ2ꢀ(4ꢀfluorophenyl)ꢀ1ꢀ
((trimethylsilyl)methyl)cyclopropane-1-carboxamide
(42bg): This compound was obtained via typical procedure A
using (trimethylsilyl)methylmagnesium chloride (300 ꢁL, 1.3
M in THF, 0.390 mmol, 1.3 equiv.) and N,Nꢀdiethylꢀ1,2ꢀ
diphenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (38b) (88.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
matography on silica gel eluting with a mixture of hexane and
ethyl acetate (6:1). The titled compound was obtained as a
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (38d) (93.0 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
matography on silica gel eluting with a hexane and ethyl aceꢀ
tate mixture (6:1). A mixture of inseparable regioisomers was
obtained as a colorless oil, Rf 0.16. Yield 97.0 mg, (0.298
mmol, 99%), 42da:41da ratio 95:5, dr >98:2. 1H NMR (500
MHz, CDCl3) mixture of regioisomers: δ [7.13 – 7.04 (m),
Σ4H], [7.04 – 6.99 (m), Σ1H], [6.92 – 6.86 (m), Σ2H], [6.79 –
6.73 (m) & 6.71 – 6.65 (m), Σ2H], [3.67 (dq, J = 14.4, 7.1 Hz)
& 3.58 (dq, J = 13.8, 7.1 Hz) & 3.12 (dq, J = 13.9, 7.0 Hz) &
3.04 (dq, J = 14.0, 7.0 Hz), Σ4H], [2.97 (d, J = 6.6 Hz) & 2.38
– 2.31 (m) & 2.07 (d, J = 5.5 Hz) & 1.45 (d, J = 5.3 Hz),
Σ2H], [1.58 (s) & 1.30 (d, J = 6.2 Hz), Σ3H], [1.11 (t, J = 7.1
Hz), Σ3H], [0.84 (t, J = 7.1 Hz) & 0.39 (t, J = 7.0 Hz), Σ3H];
13C NMR (126 MHz, CDCl3) major regioisomer: δ 170.1,
161.1 (d, J = 243.9 Hz), 136.9, 133.3 (d, J = 2.8 Hz), 129.9 (+,
d, J = 8.1 Hz, 2C), 128.7 (+), 128.2 (+, 2C), 126.5 (+, 2C),
114.4 (+, d, J = 21.5 Hz, 2C), 44.5, 41.4 (ꢀ), 39.7 (ꢀ), 35.8 (+),
21.4 (+), 14.3 (+), 12.5 (+), 12.5 (+); FT IR (KBr, cmꢀ1):
2969, 2934, 2872, 1629, 1512, 1426, 1216, 822, 761, 700;
o
colorless solid, mp 186.8 – 187.4 C, Rf 0.30. Yield 79.4 mg
(0.209 mmol, 70%), 42bg:41bg ratio >98:2, dr >98:2. 1H
NMR (500 MHz, CDCl3) δ 7.07 (d, J = 4.3 Hz, 4H), 7.04 –
6.90 (m, 6H), 3.71 (dq, J = 14.3, 7.1 Hz, 1H), 3.54 (dq, J =
13.9, 7.1 Hz, 1H), 3.18 (dq, J = 13.9, 7.0 Hz, 1H), 3.05 (dq, J
= 14.0, 7.0 Hz, 1H), 2.98 (d, J = 6.8 Hz, 1H), 2.35 (ddd, J =
12.3, 6.8, 2.7 Hz, 1H), 1.12 (t, J = 7.1 Hz, 3H), 1.05 (dd, J =
14.4, 2.7 Hz, 1H), 0.41 – 0.35 (m, 1H), 0.38 (t, J = 7.1 Hz,
3H), 0.09 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 170.5,
137.5, 137.3, 128.9 (+, 2C), 128.5 (+, 2C), 128.1 (+, 2C),
127.6 (+, 2C), 126.3 (+), 125.6 (+), 45.0, 41.5 (ꢀ), 39.8 (ꢀ),
37.1 (+), 22.7 (+), 16.4 (ꢀ), 12.7 (+), 12.5 (+), ꢀ1.2 (+, 3C); FT
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The Journal of Organic Chemistry
2ꢀeneꢀ1ꢀcarboxamide (38a) (88.0 mg, 0.30 mmol, 1.0 equiv.)
HRMS (TOF ES): Found 348.1744, calculated for
1
2
3
4
5
6
7
8
C21H24FNONa (M+Na) 348.1740 (1.1 ppm).
was then added slowly dropwise as a solution in dry THF (2
mL). After 20 minutes of stirring at 0 oC, iodomethane (28 ꢁL,
64.0 mg, 0.45 mmol, 1.50 equiv.) was added dropwise and
(1S*,2R*,3S*)-N,N-Diethyl-2-(4-methoxyphenyl)-3-
methyl-1-phenylcyclopropane-1-carboxamide (42ea) and
(1R*,2R*)-N,N-diethyl-2-(4-methoxyphenyl)-2-methyl-1-
phenylcyclopropane-1-carboxamide (41ea). These comꢀ
pounds were obtained via typical procedure A using methylꢀ
magnesium bromide (130 ꢁL, 3.0 M in THF, 0.390 mmol,
1.30 equiv.) and N,Nꢀdiethylꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀ
phenylcyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (38e) (96.5 mg, 0.30
mmol, 1.0 equiv.). The product was purified by column chroꢀ
matography on silica gel eluting with a hexane and ethyl aceꢀ
tate mixture (3:1). A mixture of inseparable regioisomers was
obtained as a colorless oil, Rf 0.23. Yield 52.2 mg, (0.155
mmol, 52%), 42ea:41ea ratio 90:10, dr >98:2. 1H NMR (500
MHz, CDCl3) δ 7.12 – 7.06 (m, 4H), 7.05 – 6.98 (m, 1H), 6.86
(d, J = 8.6 Hz, 2H), 6.56 (d, J = 8.6 Hz, 2H), 3.73 – 3.66 (m,
1H), 3.65 (s, 3H), 3.58 (dq, J = 14.0, 7.1 Hz, 1H), 3.13 (dq, J
= 14.0, 7.0 Hz, 1H), 3.04 (dq, J = 14.0, 6.9 Hz, 1H), 2.94 (d, J
= 6.6 Hz, 1H), 2.40 – 2.25 (m, 1H), 1.29 (d, J = 6.2 Hz, 3H),
1.11 (t, J = 7.0 Hz, 3H), 0.40 (t, J = 7.0 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 170.4, 157.6, 137.3, 129.7, 129.5 (+,
2C), 128.8 (+, 2C), 128.2 (+, 2C), 126.3 (+), 113.1 (+, 2C),
55.2 (+), 44.4, 41.4 (ꢀ), 39.7 (ꢀ), 35.9 (+), 21.4 (+), 14.4 (+),
12.6 (+), 12.5 (+); FT IR (KBr, cmꢀ1): 3057, 2965, 2934,
2871, 1628, 1515, 1426, 1277, 1247, 1036, 821, 756, 700;
HRMS (TOF ES): Found 360.1927, calculated for
C22H27NO2Na (M+Na) 360.1939 (3.3 ppm).
o
stirred for 30 minutes at 0 C. The reaction was then allowed
to warm to room temperature over 15 min before saturated
aqueous ammonium chloride (1 mL) was added. The resulting
solution was then diluted with water and extracted with diethyl
ether (3 x 5 mL). Combined organic layers were washed with
brine, dried, filtered, and evaporated. The product was purified
by column chromatography on silica gel eluting with a mixꢀ
ture of hexane and ethyl acetate (6:1). The titled compound
9
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
was obtained as a colorless solid, mp 150.3 – 151.2 C, Rf
0.26. Yield in 87.5 mg yield (0.272 mmol, 91 %), dr >98:2.
1H NMR (500 MHz, CDCl3) δ 7.08 – 6.97 (m, 8H), 6.96 –
6.90 (m, 2H), 3.67 – 3.51 (m, 2H), 3.21 – 3.03 (m, 2H), 2.39
(q, J = 6.5 Hz, 1H), 1.61 (s, 3H), 1.36 (d, J = 6.5 Hz, 3H), 1.12
(t, J = 7.1 Hz, 3H), 0.44 (t, J = 7.1 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 169.5, 144.9, 138.7, 129.4 (+, 2C), 127.9 (+,
2C), 127.8 (+), 127.7 (+, 2C), 125.9 (+, 2C), 125.5 (+), 42.4,
41.6 (ꢀ), 38.7 (ꢀ), 38.2, 23.5 (+), 21.5 (+), 12.7 (+), 12.7 (+),
10.5 (+); FT IR (KBr, cmꢀ1): 3059, 2969, 1624, 1444, 1422,
1267, 1066, 694; HRMS (TOF ES): Found 344.1996, calcuꢀ
lated for C22H27NONa (M+Na) 344.1990 (1.7 ppm).
ASSOCIATED CONTENT
Supporting Information
Spectral data (PDF)
XꢀRay crystallography data (CIF)
(1S*,2S*,3R*)-N,N-Diethyl-2-methyl-1-phenyl-3-(4-
(trifluoromethyl)phenyl)cyclopropane-1-carboxamide
(42fa): This compound was obtained via typical procedure A
using methylmagnesium bromide (130 ꢁL, 3.0M in THF,
0.390 mmol, 1.30 equiv.) and N,Nꢀdiethylꢀ1ꢀphenylꢀ2ꢀ(4ꢀ
(trifluoromethyl)phenyl)cyclopropꢀ2ꢀeneꢀ1ꢀcarboxamide (38f)
(108 mg, 0.30 mmol, 1.0 equiv.). The product was purified by
column chromatography on silica gel eluting with a mixture of
hexane and ethyl acetate (3:1). The titled compound was obꢀ
tained as a colorless solid, mp 93.9 – 94.8 oC, Rf 0.29. Yield
104.3 mg (0.278 mmol, 93%), 42fa:41fa >98:2, dr >98:2. 1H
NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.3 Hz, 2H), 7.14 –
7.06 (m, 4H), 7.06 – 7.01 (m, 1H), 7.02 (d, J = 8.3 Hz, 2H),
3.68 (dq, J = 14.3, 7.1 Hz, 1H), 3.58 (dq, J = 14.1, 7.1 Hz,
1H), 3.17 – 3.01 (m, 2H), 3.05 (d, J = 6.6 Hz, 1H), 2.47 – 2.38
(m, 1H), 1.32 (d, J = 6.2 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H),
0.40 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 169.6,
141.9, 136.3, 128.7 (+), 128.5 (+, 2C), 128.3 (+, 2C), 127.7 (q,
J = 32.0 Hz), 126.7 (+, 2C), 124.4 (q, J = 3.7 Hz, +, 2C),
124.3 (q, J = 271.7 Hz), 45.3, 41.3 (ꢀ), 39.7 (ꢀ), 36.1 (+), 21.7
(+), 14.1 (+), 12.4 (+), 12.4 (+); 19F NMR (376 MHz, CDCl3)
δ ꢀ62.34 (s, 3F); FT IR (KBr, cmꢀ1): 2972, 2936, 1630, 1326,
1164, 1121, 1068, 1017, 860, 728, 701; HRMS (TOF ES):
Found 398.1719, calculated for C22H24F3NONa (M+Na)
398.1708 (2.8 ppm).
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: mrubin@ku.edu; Fax: +1(785) 864ꢀ5396; Tel: +1 (785)
864ꢀ5071
ORCID
Andrew Edwards: 0000ꢀ0002ꢀ1278ꢀ5293
Michael Rubin: 0000ꢀ0002ꢀ1668ꢀ9311
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This project was supported by grants from the Ministry of Educaꢀ
tion and Science of the Russian Federation (MR) (Grant number
4.1196.2017/4.6). Support for NMR instruments used in this proꢀ
ject was provided by NIH Shared Instrumentation Grant No.
S10RR024664 and NSF Major Research Instrumentation Grant
No. 0329648.
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Methylꢀ
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