IMDAF Cascade Approach toward the Synthesis of the Alkaloid (±)-Minfiensine

Article abstract of DOI:10.1021/acs.joc.6b00771

The total synthesis of the Strychnos alkaloid (±)-minfiensine was achieved via an intramolecular amidofuran Diels-Alder cycloaddition/rearrangement followed by an iminium ion/cyclization cascade sequence. This domino process provides for a rapid access to the unique 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core structure found in the alkaloid minfiensine (2). In this paper, the full account of our synthetic study is described, highlighting the successful application of the cascade sequence to form the A/B/C/D rings of (±)-minfiensine (2) in high yield. A palladium-catalyzed enolate coupling reaction was then used to furnish the final E ring and complete the total synthesis of (±)-minfiensine (2).

Full text of DOI:10.1021/acs.joc.6b00771

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Article
An IMDAF Cascade Approach Toward the
Synthesis of the Alkaloid (+/-)-Minfiensine
Carolyn A Leverett, Gang Li, Stefan France, and Albert Padwa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00771 • Publication Date (Web): 23 May 2016
Downloaded from http://pubs.acs.org on May 25, 2016
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An IMDAF Cascade Approach Toward the Synthesis
of the Alkaloid (±)-Minfiensine
Carolyn A. Leverett, Gang Li, Stefan France, and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
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TOC Graphic
R2
N
OH
+
O
∆
,H
step
NHR1 cascade
steps
A
C
D
3
B
N
O
N R1
E
N
N
H
R2
CH2
Me
(
±)-minfiensine
Abstract: The total synthesis of the Strychnos alkaloid (±)-minfiensine was achieved
via an intramolecular amidofuran Diels-Alder (IMDAF) cycloaddition/rearrangement
followed by an iminium ion/cyclization cascade sequence. This domino process
provides for a rapid access to the unique 1,2,3,4-tetrahydro-9a,4a-iminoethano-
carbazole core structure found in the alkaloid minfiensine (2). In this paper the full
account of our synthetic study is described, highlighting the successful application of
the cascade sequence to form the A/B/C/D rings of (±)-minfiensine (2) in high yield. A
palladium-catalyzed enolate coupling reaction was then used to furnish the final E
ring and complete the total synthesis of (±)-minfiensine (2).
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Introduction
The Strychnos class of alkaloids, especially known for the presence of a vast
array of interesting indole-based structures, have been isolated from a variety of
natural sources and has been of long-standing interest to the synthetic community
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due to their interesting biological activities and challenging chemical complexity. In
1989, Massiott and coworkers isolated minfiensine (2) from the African plant
Strychnos minfiensis. The structure of this alkaloid was determined by NMR studies
and was shown to contain the structurally unique 1,2,3,4-tetrahydro-9a,4a-
2
iminoethanocarbazole skeleton (1) ( Figure 1). While this tetracyclic structure is
unprecedented in the Strychnos class, it is found to be more prevalent in the
akuammiline skeleton of alkaloids, appearing in the structurally-related alkaloids
vincorine 3 and echitamine 4 (Figure 1). This type of molecular assemblage is
3
recognized for its important role in traditional medicine. Not surprisingly, due to the
wide variety of biological properties they exhibit (i.e. anti-inflammatory, anti-bacterial,
anti-cancer, and anti-malarial activity)3a interest in the synthesis of the akuammiline
alkaloids and related natural products containing the 1,2,3,4-tetrahydro-9a,4a-
iminoethanocarbazole core structure has grown in recent years and provides the
Figure 1. Core Skeleton of Akuammiline Alkaloids
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OH
9
a
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D
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B
N
4a
E
N
N
H
H N
H
Me
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2
; minfiensine
1
; 9a,4a-iminoethano-carbazole
CO Me
2
CO Me
2
HO
MeO
+
N
N
N
N
Me
H
Me
Me
OH
Me
3
; vincorine
4; echitamine
synthetic community with significant challenges due to their unique chemical
complexity.4
The first total synthesis of (+)-minfiensine (2) was reported by Overman and
coworkers and utilized a sequential enantioselective intramolecular Heck/iminium ion
addition sequence to generate the 1,2,3,4-tetrahydro-9a,4a-iminoethano-carbazole
5
core. The Overman group then demonstrated that two types of palladium-mediated
routes can be used to prepare the natural product, one involving a Heck cyclization
and the other a palladium-catalyzed enolate coupling to generate the pentacyclic
framework. Soon thereafter, Qin and coworkers developed a three-step, one-pot
cyclopropane-mediated route to the core of (±)-minfiensine (2).6 Closure of the final
E-ring was carried out via a palladium-catalyzed enolate coupling reaction similar to
5
that used by Overman. Wang and coworkers then reported on a transition metal
7
catalyzed reaction as the key step in a formal synthesis of (±)-minfiensine (2). This
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approach relied on a gold-catalyzed tandem cyclization to generate a key
intermediate that had been employed in Overman’s pioneering synthesis of (+)-
minfiensine (2). Another route to (±)-minfiensine (2) was subsequently described by
Qiu and coworkers and began with a Fischer indole reaction to generate the indolone
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skeleton. This was followed by a palladium-catalyzed allylation sequence for
installation of the quaternary stereocenter present in minfiensine (2).The Macmillan
group also completed an efficient 9-step synthesis of (+)-minfiensine (2) which relied
on a unique organo-catalyzed route to generate the natural product. This was
accomplished from a Boc-tryptamine intermediate via an organo-catalyzed Diels-
Alder cycloaddition/amine cyclization.9
While a plethora of routes to minfiensine (2) exists,10 we recognized that it
would be desirable to develop a general and high yielding method to prepare the
important 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core 1 found in quite a
number of different alkaloids. For some time our research group has been utilizing the
intramolecular furan Diels-Alder (IMDAF) reaction to prepare a wide assortment of
complex natural products.11 As a result of these studies, we envisioned a synthesis
of minfiensine that would proceed via an IMDAF reaction of an appropriately
substituted amidofuran12 followed by an acid-catalyzed iminium-ion/addition
sequence (vide infra) to generate the natural product. Herein we provide a full
account of our studies towards a successful construction of (±)-minfiensine (2) that
proceeds by use of the above protocol for its synthesis.13
Results and Discussion
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In a series of earlier papers from our research group, we had demonstrated
the utility of the intramolecular furan Diels-Alder (IMDAF) rearrangement cascade of
amidofurans to prepare several alkaloids.11 Thus, heating amidofurans 5 and 8
produced tetrahydroindolinone intermediates 6 and 9, which in turn were employed to
achieve the total syntheses of (±)-mesembrane 7 and (±)-crinane 10 (Scheme 1).14
Scheme 1
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Ar
Ar
O
N
heat
O
N
CO Et
2
CO Et
2
5; Ar = 3,4-dimethoxyphenyl
6; Ar = 3,4-dimethoxyphenyl
8;
Ar = benzo[d][1,3]dioxol-5-yl
9;
Ar = benzo[d][1,3]dioxol-5-yl
OMe
OMe
O
N
)-crinane
O
N
10; (
±
H
Me
7; (±)-mesembrane
We thought that by employing amidofuran 14 as the starting substrate
(
Scheme 2), we would be able to promote the formation of tetrahydroindolinone 13b,
which represents the C/D core portion of minfiensine (2). From this key intermediate,
we believed that an acid-promoted addition of the tethered aryl amine 13b onto a
transient iminium ion would generate the B ring present in the 1,2,3,4-tetrahydro-
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a,4a-iminoethano-carbazole core 12. Installation of the final E ring could be induced
to proceed by a palladium-catalyzed enolate cyclization of 11,15 under conditions
similar to those previously described in our synthesis of strychnine.16
Scheme 2
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OH
O
O
A
C
D
B
N
N
E
N R1
N
N
H
N
I
H
R2
Me
Me
11
12
2; (±)-minfiensine
+
H
R2
NHR2
NHR2
O
O
O
N
heat
N
N
R1
R1
R1
1
3a
13b
14
Earlier results from our laboratory showed that the thermolysis of an amido
furan such as 20 afforded tetrahydroindoline 24 in excellent yield.14 On the basis of
these earlier investigations we decided to begin our studies toward minfiensine (2) by
first making using of the o-nitro aryl substrate 21,17 which we believed could be readily
reduced to the desired aniline after the key IMDAF cycloaddition reaction (Scheme 3).
The desired amidofuran 21 was readily obtained by a Suzuki cross-coupling reaction
of the commercially available boronic acid 15 with vinyl iodide 17,18 thereby
generating compound 18 in good yield. From 18, the alcohol moiety was converted
into the corresponding mesylate and a subsequent displacement with the amido anion
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derived from ethyl furan-2-yl carbamate led to the desired cycloaddition precursor 21.
Unfortunately, all of our attempts to induce the IMDAF cycloaddition of 21, even at
temperatures up to 200 °C, led to only recovered starting material. Using some
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2 4
conditions previously described by Heathcock (Cu(acac) , NaBH
, EtOH),19 reduction
of the nitro group in 21 was cleanly achieved in near quantitative yield. Once again,
our efforts to induce an IMDAF cycloaddition of furan 22 also failed to produce any
characterizable product. We also prepared the o-bromo-aryl furan 23 and in this case,
a 61% yield of the desired tetrahydroindolinone intermediate 27 was obtained, but only
by extensive heating for six days at 200 °C.
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Scheme 3
R1
I
OH
R1
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7
OH
CH2
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B(OH)2
CH2
Pd(PPh3)4
Na CO
15; R = NO
1
2
2
3
18; R = NO
1
6; R = Br
1
2
1
19; R = Br
1
MsCl, NEt3
O
NHCO Et
2
TBAHS
NaOH, K CO
2
3
R1
R1
H C
O
2
o
O
1
85-200 C
N
N
CO Et
2
CO Et
2
2
2
2
2
0; R = H
1; R = NO
2; R = NH
3; R = Br
24; R = H
1
1
2
2
2
5; R = NO (no reaction)
6; R = NH (no reaction)
7; R = Br (61%)
1
2
2
1
2
1
1
2
1
1
Considering our previous success with the IMDAF reactions of the related m-
and p-substituted systems (i.e., Scheme 1),14 we suspected that the presence of a
substituent in the o-position of the aromatic ring resulted in an unfavorable steric
interaction in the required Diels-Alder transition state for the above cycloadditions,
thereby diminishing the overall rate of the IMDAF reaction. Even though tetrahydro-
indolinone 27 could be obtained in somewhat reasonable yield, the required reaction
conditions were certainly less than desirable for throughput of material in order to
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complete a total synthesis of (±)-minfiensine (2). At this point in time, we decided to
make use of some information derived from some earlier work which showed that a
significant enhancement of rate occurred when 2-imino-furans were used as
substrates.20 This substantial rate enhancement in the intramolecular 4+2-
cycloaddition is most likely due to a conformational change which results by
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Scheme 4
CO Et
2
o
N
200 C
No Cycloaddition
X
O
10 h
CH2
2
2
8; X = H, H
9; X = O
o
1
00 C
2
h
N
CO Et
2
O
30 (90%)
installation of a carbonyl group in the tether between the diene and dienophile. Our
earlier studies showed that the cycloaddition of enamido furan 28 did not occur even
upon heating at 200 °C for 10 h. The incorporation of an additional carbonyl group in
the tether as in imidofuran 29 led to a most facile cycloaddition reaction to provide 30
in 90% yield when heating 29 at 100 °C for only 2 h (Scheme 4).20 We believe that
this remarkable rate enhancement is the result of the dienophile and furanyl ring being
placed in closer proximity to each other for the cycloaddition as compared to those
systems lacking the imido carbonyl group in the tether. With this in mind, we expected
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that the IMDAF reaction of imidofuran 32 would be much more facile than the
corresponding amidofuran analog 23. Consequently we prepared imidofuran 32 by a
2
-step sequence from 3-(2-bromophenyl)but-3-enoic acid (Scheme 5). To our delight,
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the Diels-Alder cycloaddition/rearrangement cascade of 32 to 34 occurred in 90% yield
when heated at 150 °C for only 10 h.
Scheme 5
CO Et
i-butyl
chloroformate
2
Br
R1
N
O
H C
2
OH
heat
O
O
O
O
N
NLiCO Et
2
O
CH2
N
CO Et
2
3
6
3
2; R = Br
1
33; R = N
1
3
o
150 C
CO Et
2
NHR2
O
Br
N
O
O
O
O
O
N
N
H
N
CO Et
2
37
CO Et
2
3
5
3
4; 90%
With a reasonable route now available for accessing the bromo-containing
tetrahydroindolinone core 34, we decided to pursue the installation of the anilino group
which was necessary for our planned iminium-ion cyclization. Unfortunately, all the
conditions we tried for the conversion of the bromo-substituted imidofuran 34 to the
corresponding amino derivative 35 were unsuccessful.21 As an alternative approach,
we considered using the azido furan 33, which we hoped would be readily converted to
the desired aromatic amine through azide reduction after the IMDAF cycloaddition.
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However, the results were once again disappointing, as only 3-substituted indole 37
was observed upon heating rather than the desired Diels-Alder/rearrangement product
(
Scheme 5). Mechanistically indole 37 is thought to be formed via nitrogen extrusion,
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electrocyclization, and a subsequent 1,5-hydrogen shift.22
We next examined the direct reduction of azido imidofuran 33 using traditional
azide zinc-mediated or Staudinger23 reduction conditions (Zn/acid or PPh
Scheme 6) so as to prepare the desired arylamine. However, when azide 33 was
3
2
/H O)
(
submitted to various Zn/acid conditions, azide reduction was rapidly followed by
cyclization and displacement of the furanyl carbamate to provide lactam 38. This
transient species then underwent a further 1,3-hydrogen shift to eventually give 4-
3
methylquinolin-2(1H)-one (39). Additional attempts to reduce azide 33 with PPh /THF
did give the expected iminophosphorane 40, but this transient intermediate rapidly
reacted with the adjacent imido carbonyl group via an aza- Wittig24 reaction to produce
dihydroquinoline 41 which rapidly isomerized with a trace of acid to the more stable
quinoline 42 (Scheme 6).
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6
Scheme 6
H
N
H
N3
+
N
O
O
Zn (H )
H C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
rt
O
O
N
CH
CH2
3
CO Et
2
3
9
38
33
rt Ph P/THF, H+
3
CH2
N
CH
3
Ph P N
3
H C
2
CO Et
CO Et
2
2
O
N
O
N
N
N
O
O
CO Et
2
40
42
41
It became clear to us at this point in time that the presence of a substituent
group in the ortho position of the aromatic ring of the amidofuranyl system
significantly diminished the rate of the critical IMDAF cycloaddition in our first-
generation approach toward minfiensine (2). To avoid this obstacle, a second-
generation IMDAF approach was developed and this involved a thermal IMDAF
cycloaddition of the related aminofuran 43. Our retrosynthetic plan for this new
direction is outlined in Scheme 7. In this modified route, we believed that we could
access the A/B/C tricyclic intermediate 44 via an IMDAF/rearrangement cascade of
4
3. This proposed approach would alleviate the problematic pathways encountered
in our first generation route. Furthermore, we envisioned that this cascade
sequence could be combined with a subsequent iminium-ion cyclization to form the
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D ring present in intermediate 12, thereby providing a rapid path toward the
synthesis of (±)-minfiensine (2).
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 7
OH
O
O
A
C
D
B
N
N
E
N R1
N
N
H
N
I
H
R2
Me
Me
11
12
2; (±)-minfiensine
+
H
R NH
1
R2
O
N
O
NHR1
heat
N
CH2
R2
4
4
4
3
In order to ascertain the feasibility of this approach, we decided to first
examine the cyclization of a model substrate (Scheme 8). Our initial attempts to
prepare furan 51 by a palladium-catalyzed coupling of 2-bromofuran 46 with aryl
amine 45 did not give the desired Buchwald-Hartwig coupling product 51. Instead,
we believe that a competitive Heck coupling reaction occurred across the vinyl
group to produce intermediate 47, which was eventually converted to quinoline 50
via the spirocyclic intermediate 49. As a consequence of this competitive Heck
reaction, we opted to prepare the desired model amidofuran system by reacting
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 8
OTBS
Boc N
CH2
5
1 (not observed)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
Pd(0)
O
Pd(0)
Heck
OTBS
+
Br
OTBS
BocHN
CH2
BocHN
O
46
45
4
7
TBAF
TFA
CH CH OH
2
2
CH CH OH
CH CH OH
2
2
2
2
+
O
CH OH
2
O
N
H
N
NH2
50
49
48
furanyl carbamates 52b (and 53) with aryl iodide 52a (Scheme 9) in the presence of
a transition metal catalyst. We were pleased to note that amidofurans 54 and 55
were formed in good yield when the reaction was carried out employing Buchwald’s
copper-catalyzed amidation protocol using copper(I)-thiophene-2-carboxylate
2 3
CuTC)/Cs CO
as the catalyst.25 Submission of both of these substrates to
(
standard olefination conditions26 provided the model cycloaddition precursors 56
0
and 57. Upon heating at 100 C, these precursors underwent the desired IMDAF
rearrangement cascade to give tetrahydroindolinone intermediates 58 and 59 in
8
0% yield.
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9
Scheme 9
O
I
O
CuTC
Cs CO3
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
NHCO R
2
NCO R
2
+
Me
2
Me
44-48%
O
52b; R = C H5
53; R = t-Bu
2
5
2a
O
54; R = C H5
2
55; R = t-Bu
CH I , Zn
62-66%
2 2
PbCl , TiCl4
2
O
O
Me
heat
NCO R
2
8
0%
Me
N
CH2
CO R
2
5
8; R = C H5
56; R = C H5
2
2
59; R = t-Bu
57; R = t-Bu
ꢀ
ꢀ
With this positive result in hand from the model systems, we proceeded with
our synthesis of minfiensine by preparing the necessary Diels-Alder cycloaddition
precursor. Submission of commercially available boronate ester 60 to Suzuki-
Miyaura cross coupling conditions with vinyl iodide 17 resulted in the formation of
the desired styrenyl alcohol intermediate 61 in good yield. Standard mesylation of
61 was followed by a subsequent displacement with allylamine to give 63 in 72%
yield. Installation of the t-Boc from 63 proceeded in 74% yield to afford 64. Once
2 3
again we found the Buchwald’s (CuTC)/Cs CO coupling conditions to be optimal,
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
as smooth coupling of acyl amine 64 and 2-bromofuran 46 occurred at 90 °C.
Under these conditions the initially formed amidofuran spontaneously underwent
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 10
Me
O
Me
O
(
Ph P) Pd
3 4
NH
NH
Na CO3
2
X
O
B
I
OH
17
O
CH2
CH2
63%)
60
61; X = OH
(
MsCl, NEt3
6
2; X = OMs
(
88%)
allyl amine
(
72%)
Me
O
R
N
CuTC
NH
R
N
O
Cs CO3
2
CH2
O
Br
CH2
N
(
t-Boc) O
63; R = H
2
Me
46
O
NEt3
64; R = t-Boc
(
74%)
6
6
5; R = H (86%)
6; R = t-Boc (82%)
o
1
20 C
R
N
O
O
MgI2
N
O
N
N
CH2
Me
69 (60%)
Me
O
6
6
7; R = H
8; R = t-Boc (31%)
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the desired IMDAF cycloaddition giving rise to cycloadduct 66 which, in this case,
was isolated in 82% yield. Additional heating of oxabicycle 66 at 120 °C triggered the
expected ring-opening/rearrangement sequence, producing tetrahydroindolinone 68
in 31% yield. The unprotected amine 63 was also submitted to the CuTC coupling
conditions and furnished the tandem coupling/Diels-Alder cycloaddition product 65 in
86% yield. To our delight, when oxabicycle 65 was heated at 120 °C in the presence
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
2
of MgI , the required ring opening/rearrangement sequence took place which was
then followed by a subsequent iminium-ion cyclization cascade, all in one pot, to
provide 69 from 63 in 60% overall yield (Scheme 10).
With the tetracyclic intermediate 69 on hand, we focused our efforts on
completing the synthesis of (±)-minfiensine (2). This was accomplished by removal of
the allyl groupl27 in 69 followed by displacement of the mesylate functionality in 7128
with the secondary amino group in 70 to produce vinyl iodide 72. Treatment of 72
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 11
O
O
K CO
2
3
I
N
I
N
MsO
N
R
N
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
71
O
C
Me
Me
Me
H
72; 65%
6
9; R = allyl
Pd(0)
5%
8
70; R = H
Pd(0)
K CO
2
3
67%
OTf
O
NaHMDS
ArNTf2
N
Me
Me
N
9
3%
N
N
Me
O
Me
O
7
4
7
3
n-Bu SnCH OH
3
2
Pd(0)
6
1%
NH NH2
2
OH
OH
Me
78%
N
Me
N
H
N
N
O
Me
2
; (±)-minfiensine
75
under Pd-catalyzed enolate coupling conditions15,16 (PdCl
(dppf)⋅CH
Cl
, K
CO
) led
2
2
2
2
3
to the advanced intermediate 73 in good yield, thereby providing the structural
framework of minfiensine. Enol triflate formation via the Comins reagent (ArNTf
2
,
NaHMDS) afforded 74, which smoothly underwent a Stille cross-coupling reaction
with tri-n-butylstannylmethanol29 to give the N-acylated minfiensine derivative 75.
Acyl group deprotection with hydrazine provided the natural product (±)-minfiensine
(
2) in 78% yield. (Scheme 11).
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9
In conclusion, in this article we have described our successful approach
towards the total synthesis of the Strychnos alkaloid (±)-minfiensine by utilizing a
one-pot intramolecular amidofuran [4+2]-cycloaddition (IMDAF) rearrangement
/iminum-ion-cyclization cascade sequence as the key step to generate the A/B/C/D
rings present in (±)-minfiensine. From this core structure, closure of the final E ring
was accomplished by a palladium-catalyzed coupling of the tethered vinyl iodide
and the keto-enolate. This work not only provides a versatile route to the complex
and unique 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core structure present in
minfiensine, but also has the potential to provide access to other structurally related
alkaloids.
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
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Experimental Section
General Procedures. Melting points are uncorrected. Mass spectra were
determined at an ionizing voltage of 70eV. The mass analyzer type used for the
HRMS measurements was TOF with electrospray as the ionization method. Unless
otherwise noted, all reactions were performed in flame-dried glassware under an
atmosphere of either dry nitrogen or argon. All solvents were distilled prior to use.
Solutions were evaporated under reduced pressure with a rotary evaporator and the
residue was chromatographed on a silica gel column (0.04-0.062 mm) using an
ethyl acetate/hexane mixture as the eluent unless specified otherwise. All solids
were recrystallized from ethyl acetate/hexane for analytical data. Yields refer to
isolated, spectroscopically pure compounds.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethyl Furan-2-yl-(3-(2-nitrophenyl)but-3-enyl)carbamate (21). To a stirred solution
18
containing (2-nitrophenyl)boronic acid (0.6 g, 3.6 mmol), and 3-iodobut-3-en-1-ol (0.59
g, 3.0 mmol), benzene (30 mL), EtOH (15 mL), and 2 M aqueous Na CO (15.2 mL) was
2
3
o
added Pd(PPh ) (0.14 g, 0.06 mmol) and the reaction mixture was heated to 65 C for
3
4
1
2 h. After cooling to room temperature, the mixture was diluted with ether and washed
with brine, dried over MgSO , filtered, and concentrated under reduced pressure. The
4
resulting residue was purified by column chromatography to provide 0.37 g (64%) of 3-(2-
nitrophenyl)but-3-en-1-ol (18) as a yellow oil; IR (thin film) 3376, 2950, 2882, 1608, 1571,
-1 1
1
526, 1349, 048, 911, 787, 762, and 721 cm ; H-NMR (CDCl , 400 MHz) δ 2.68-2.71
3
(
m, 2H), 3.71 (t, 2H, J = 6.0 Hz), 5.07 (s, 1H), 5.29 (d, 1H, J = 0.8 Hz), 7.35 (dd, 1H, J =
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7
.6 Hz and 1.2 Hz), 7.41-7.45 (m, 1H), 7.56 (dt, 1H, J = 7.6 and 1.2 Hz), and 7.84-7.86
1
3
(m, 1H); C-NMR (CDCl , 100 MHz) δ 40.5, 60.6, 117.6, 124.5, 128.4, 130.8, 132.8,
3
1
37.4, 143.2, and 149.1.
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
To a stirred solution of the above alcohol (0.16 g, 0.83 mmol) and
o
methanesulfonyl chloride (0.07 mL, 0.91 mmol) in CH Cl (20 mL) at 0 C was added
2
2
o
triethylamine (0.14 mL, 1.0 mmol) and the resulting mixture was stirred for 1 h at 0 C.
The mixture was then diluted with H O and extracted with CH Cl and the organic layer
2
2
2
was dried over MgSO , filtered, and concentrated under reduced pressure. The residue
4
was chromatographed on silica gel to provide 0.17 g (74%) of 3-(2-nitro-phenyl)but-3-enyl
methanesulfonate as a pale yellow oil; IR (thin film) 3031, 2941, 1638, 1608, 1571, 1526,
-1 1
1
352, 1175, 960, 913, and 790 cm ; H-NMR (CDCl , 400 MHz) δ 2.86 (dt, 2H, J = 6.8
3
and 0.8 Hz), 2.97 (s, 3H), 4.31 (t, 2H, J = 6.8 Hz), 5.11 (s, 1H), 5.31 (d, 1H, J = 0.8 Hz),
7.34 (dd, 1H, J = 7.6 and 1.6 Hz), 7.44-7.48 (m, 1H), 7.59 (dt, 1H, J = 7.6 and 1.2 Hz),
1
3
and 7.92 (dd, 1H, J = 8.0 and 1.2 Hz); C-NMR (CDCl , 100 MHz) δ 36.5, 37.6, 67.7,
3
1
17.9, 124.6, 128.8, 131.4, 133.3, 137.0, 142.0, and 148.3.
30
A solution of ethyl furan-2-ylcarbamate (0.04 g, 0.24 mmol), K CO (0.08 g,
2
3
0
.48 mmol), tetrabutylammonium hydrogensulfate (0.015 g, 0.044 mmol), and freshly
powdered NaOH (33 mg, 0.82 mmol) in benzene (10 mL) was heated at reflux for 30 min.
The mixture was cooled to room temperature and a solution containing the above
mesylate (0.08 g, 0.29 mmol) in benzene (3 mL) was added. The mixture was heated at
o
8
0 C for 1 h and was then cooled to rt, diluted with Et O, and quenched with H O. The
2 2
aqueous layer was extracted with Et O and the organic layer was washed with a
2
saturated aqueous NaHCO solution, dried over MgSO , filtered, and concentrated under
3
4
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reduced pressure. The residue was subjected to column chromatography to provide 0.05
g (60%) of the titled compound 21 as a pale yellow oil; IR (thin film) 3085, 2983, 2935,
-1 1
1
4
717, 1610, 1527, 1350, 1297, 1378, 1195, 1145, 911, and 765 cm ; H-NMR (CDCl ,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
00 MHz) δ 1.21 (t, 3H, J = 6.8 Hz), 2.66 (t, 2H, J = 7.6 Hz), 3.70-3.74 (m, 2H), 4.15 (q,
2H, J = 14.0 and 6.8 Hz), 5.04 (s, 1H), 5.23 (d, 1H), 6.01 (brs, 1H), 6.34-6.36 (m, 1H),
7
1
.19 (s, 1H), 7.30-7.32 (m, 1H), 7.40-7.44 (m, 1H), 7.53-7.57 (m, 1H), and 7.88-7.90 (m,
1
3
H); C-NMR (CDCl , 100 MHz) δ 14.6, 35.8, 48.0, 62.4, 102.0, 111.2, 116.5, 124.4,
3
128.4, 131.3, 132.8, 138.0, 138.7, 144.2, 148.1, 148.8, and 155.0.
All of our attempts to induce the IMDAF cycloaddition of 21, even at temperatures
up to 200 °C, led to only recovered starting material.
Ethyl 3-(2-aminophenyl)but-3-enyl-(furan-2-yl)carbamate (22). To a stirred solution of
Cu(acac) (22 mg, 0.085 mmol) in absolute EtOH (5.7 mL) was added NaBH (0.1 g, 2.8
2
4
mmol). The reaction mixture changed color from purple to brown. The mixture was stirred
at rt for 25 min, during which time the color turned clear and a brown precipitate formed.
A solution of the above furanyl amide 21 (0.09 g, 0.28 mmol) in THF (5.7 mL) was added
and the resulting mixture was stirred for 1.25 h at rt. The mixture was then poured into a
saturated aqueous NaHCO solution and extracted with CHCl . The resulting organic
3
3
layer was dried over MgSO , filtered, and concentrated under reduced pressure to
4
provide 0.08 g (93%) of the titled compound 22; IR (thin film) 3447, 3369, 2980, 2931,
-
1 1
1713, 1615, 1495, 1409, 1379, 1298, 1194, 1155, and 1057 cm ; H-NMR (CDCl , 400
3
MHz) δ 1.21 (t, 3H, J = 7.2 Hz), 2.65 (d, 1H, J = 6.8 Hz), 2.67 (d, 1H, J = 8.4 Hz), 3.68-
3
.72 (m, 2H), 4.15 (q, 2H, J = 7.2 Hz), 5.16 (d, 1H, J = 1.6 Hz), 5.32 (d, 1H, J = 1.6 Hz),
6.01 (brs, 1H), 6.35 (dd, 1H, J = 3.6 and 2.4 Hz), 6.68-6.74 (m, 2H), 6.97 (dd, 1H, J = 7.2
13
and 1.6 Hz), 7.06 (td, 1H, J = 7.6 and 1.6 Hz) and 7.19-7.20 (brs, 1H); C-NMR (CDCl ,
3
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7
8
9
1
1
00 MHz) δ 14.6, 36.1, 48.0, 62.5, 111.2, 115.9, 116.7, 118.5, 127.6, 128.3, 128.7, 138.3,
38.8, 143.3, 144.4, 147.9, and 155.2.
All of our attempts to induce the IMDAF cycloaddition of 22, even at temperatures
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
up to 200 °C, led to only recovered starting material.
Ethyl 3-(2-Bromophenyl)but-3-enyl-(furan-2-yl)carbamate (23). To a stirred solution of
3-iodobut-3-en-1-ol (0.59 g, 3.0 mmol) in benzene (10 mL) was added Pd(PPh ) (0.14 g,
3
4
0
.12 mmol), 2 M Na CO (12 mL), and a solution of 2-bromophenylboronic acid (16)
2 3
o
(
0.71 g, 3.5 mmol) in EtOH (15 mL). The reaction mixture was heated to 65 C for 14 h,
cooled to rt, diluted with Et O, washed with brine, dried over MgSO , filtered, and
2
4
concentrated under reduced pressure. The residue was purified by silica gel
chromatography to yield 0.67 g (79%) of 3-(2-bromophenyl)but-3-en-1-ol (19) as a yellow
-
1 1
oil; IR (thin film) 3339, 2944, 1638, 1468, 1427, 1042, 1024, 910, 761, and 733 cm ; H-
NMR (CDCl , 400 MHz) δ 2.70-2.73 (m, 2H), 3.64 (t, 2H, J = 6.0 Hz), 5.10-5.11 (m, 1H),
3
5
.35-5.36 (m, 1H), 7.12-7.19 (m, 2H), 7.26-7.30 (dt, 1H, J = 8.0 and 1.2 Hz), and 7.57
13
(
dd, 1H, J = 8.0 and 1.2 Hz); C-NMR (CDCl , 100 MHz) δ 40.5, 60.4, 118.3, 122.2,
3
1
27.5, 128.9, 130.4, 133.0, 143.1, and 146.3.
To a stirred solution of the above alcohol 19 (0.19 g, 0.82 mmol) and
o
methanesulfonyl chloride (0.07 mL, 0.9 mmol) in CH Cl (20 mL) at 0 C was added Et N
2
2
3
(
0.14 mL, 1.0 mmol) and the resulting mixture was stirred for 0.5 h. The mixture was
diluted with H O and extracted with CH Cl . The organic layer was dried over MgSO ,
2
2
2
4
filtered, and concentrated under reduced pressure. The residue was subjected to silica
gel chromatography to provide 0.27 g of 3-(2-bromophenyl)but-3-enyl methanesulfonate
as a yellow oil; IR (thin film) 2937, 1719, 1468, 1427, 1353, 1173, 1028, 958, and 910
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1 1
cm ; H-NMR (CDCl , 400 MHz) δ 2.91-2.95 (m, 5H), 4.22-4.25 (m, 2H), 5.14 (s, 1H),
3
5.36-5.37 (m, 1H), 7.14-7.18 (m, 2H), 7.27-7.31 (m, 1H), and 7.57 (d, 1H, J = 8.0 Hz);
1
3
C-NMR (CDCl , 100 MHz) δ 36.3, 37.7, 67.7, 119.1, 122.1, 127.7, 129.3, 130.8, 133.1,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
142.3, and 144.6.
A solution of ethyl furan-2-ylcarbamate (37 mg, 0.24 mmol), K CO (0.09 g, 0.53
2
3
mmol), tetrabutylammonium hydrogen sulfate (16 mg, 0.05 mmol), and freshly powdered
NaOH (33 mg, 0.82 mmol) in benzene (10 mL) was heated at reflux for 30 min. The
mixture was cooled to rt and a solution containing the above mesylate (0.09 g, 0.29
o
mmol) in benzene (3 mL) was added and the reaction mixture was then heated at 80 C
for 1 h. The mixture was cooled to rt, diluted with Et O, and quenched with H O. The
2
2
aqueous layer was extracted with Et O, washed with a saturated aqueous NaHCO
2
3
solution, dried over MgSO , filtered, and concentrated under reduced pressure. The
4
residue was subjected to column chromatography to provide 12 mg (15%) of the titled
compound 23 as a pale yellow oil; IR (thin film) 2984, 2929, 1718, 1614, 1407, 1467,
-
1 1
1
295, 1194, 1025, 911, and 734 cm ; H-NMR (CDCl , 400 MHz) δ 1.21 (t, 3H, J = 7.2
3
Hz), 2.72 (t, 2H, J = 7.6 Hz), 3.67-3.70 (m, 2H), 4.15 (q, 2H, J = 14.4 and 7.2 Hz), 5.04 (s,
1
7
H), 5.27 (d, 1H, J = 1.2 Hz), 6.02 (brs, 1H), 6.35 (m, 1H), 7.10-7.27 (m, 4H), and 7.53-
1
3
.55 (m, 1H); C-NMR (CDCl , 100 MHz) δ 14.6, 35.5, 47.7, 62.4, 102.5, 111.2, 117.4,
3
122.1, 127.4, 128.9, 130.6, 133.0, 138.8, 143.4, 146.8, 147.9, and 155.1.
Ethyl 3a-(2-Bromophenyl)-5-oxo-2,3,3a,4,5,6-hexahydro-1H-indole-1-carboxylate
(
27). A sample of N-furanyl carbamate 23 (12 mg, 0.03 mmol) in toluene (1.5 mL) was
o
heated in a sealed tube at 200 C for 6 days. The reaction mixture was cooled to rt and
concentrated under reduced pressure. The residue was purified by silica gel
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chromatography to yield 7.5 mg (61%) of the titled compound 27 as a yellow oil; IR (thin
-
1 1
film) 2984, 2927, 1715, 1672, 1408, 1326, 1175, 1140, 1024, and 763 cm ; H-NMR
(
(
CDCl , 400 MHz) δ 1.30 (brs, 3H), 2.00-2.09 (m, 1H), 2.62 (d, 1H, J = 15.2 Hz), 2.73
3
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
dd, 1H, J = 22.4 and 2.4 Hz), 2.97 (dd, 1H, J = 22.4 and 5.6 Hz), 3.14 (m, 2H), 3.78 (t,
1H, J = 9.2 Hz), 3.98 (d, 1H, J = 15.2 Hz), 4.14-4.32 (m, 2H), 6.50 (brs, 1H), 7.11 (td, 1H,
J = 7.6 and 1.6 Hz), 7.21 (td, 1H, J = 7.6 and 1.6 Hz), 7.33 (d, 1H, J = 7.6 Hz), and 7.62
1
3
(
dd, 1H, J = 8.0 and 1.2 Hz), C-NMR (CDCl , 100 MHz) δ 14.8, 35.9, 37.6, 46.8, 50.0,
3
53.2, 61.8. 102.9, 122.4, 128.1, 129.7, 130.2, 136.5, 137.0, 142.5, 153.7, and 209.0;
+
H BrNO ) + H ]: 364.0470. Found: 364.0546.
7 18 3
HRMS Calcd for [(C
1
Ethyl 3-(2-Bromophenyl)but-3-enoyl(furan-2-yl)carbamate (32). To a stirred solution
of 3-iodobut-3-en-1-ol (0.59 g, 3.0 mmol) in benzene (10 mL) was added Pd(PPh ) (0.14
3
4
g, 0.12 mmol), a 2 M Na CO solution (12 mL), and 2-bromo-phenylboronic acid (0.71 g,
2
3
o
3.5 mmol) in EtOH (15 mL). The reaction mixture was heated to 65 C for 14 h, cooled to
rt, diluted with ether, washed with brine, dried over MgSO , filtered, and concentrated
4
under reduced pressure. The residue was purified by silica gel chromatography to yield
0.67 g (79%) of 3-(2-bromophenyl)but-3-en-1-ol as a yellow oil; IR (thin film) 3339, 2944,
-
1 1
1
2
7
638, 1468, 1427, 1024, 910, and 733 cm ; H-NMR (CDCl , 400 MHz) δ 2.70-2.73 (m,
3
H), 3.64 (t, 2H, J = 6.0 Hz), 5.10-5.11 (m, 1H), 5.35-5.36 (m, 1H), 7.12-7.19 (m, 2H),
13
.26-7.30 (dt, 1H, J = 8.0 and 1.2 Hz), and 7.57 (dd, 1H, J = 8.0 and 1.2 Hz); C-NMR
(
CDCl , 100 MHz) δ 40.5, 60.4, 118.3, 122.2, 127.5, 128.9, 130.4, 133.0, 143.1, and
3
146.3.
To a stirred solution of the above alcohol (0.15 g, 0.66 mmol) in acetone (27 mL)
o
at 0 C was added freshly prepared Jones’ reagent (1.3 mL, 1.3 mmol, 1.0 M). The
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1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
resulting solution was stirred at 0 C for 1 h, then warmed to rt and stirred for an
additional 1 h. The mixture was diluted with H O and extracted with ether. The organic
2
layer was washed with brine, dried over MgSO , filtered, and concentrated under
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reduced pressure to provide 0.16 g (91%) of 3-(2-bromophenyl)-but-3-enoic acid as a
pale yellow oil requiring no further purification; IR (thin film) 3088, 2920, 1709, 1295,
-
1 1
1
025, and 759 cm ; H-NMR (CDCl , 400 MHz) δ 3.55 (d, 2H, J = 0.8 Hz), 5.23 (s, 1H),
3
5.45 (d, 1H, J = 1.2 Hz), 7.13-7.15 (m, 1H), 7.25-7.29 (m, 2H), and 7.54 (d, 1H, J = 8.4
13
Hz); C-NMR (CDCl , 100 MHz) δ 42.1, 121.1, 122.2, 127.8, 129.6, 131.7, 133.2, 142.2,
3
1
42.6, and 177.0.
To a stirred solution of ethyl furan-2-ylcarbamate (0.22 g, 1.4 mmol) in THF (7 mL)
o
at -78 C was added n-BuLi (0.6 mL, 1.5 mmol, 2.5 M in hexane) dropwise and the
o
reaction mixture was stirred at -78 C for 45 min. In a separate flask, the above
carboxylic acid (0.39 g, 1.6 mmol) was dissolved in THF (13 mL) and the mixture was
o
cooled to 0 C. 4-Methylmorpholine (0.18 mL, 1.6 mmol) and isobutyl chloroformate (0.2
mL, 1.6 mmol) was added dropwise and the solution was stirred for 5 min. The mixture
o
was filtered over Celite with THF (7 mL), the filtrate was cooled to 0 C and the
preformed furanyl lithiate was added dropwise by cannula. The resulting reaction mixture
was stirred for 30 min and quenched with H O and extracted with EtOAc. The organic
2
layer was washed with a saturated aqueous NaHCO solution, dried over MgSO ,
3
4
filtered, and concentrated under reduced pressure. The residue was purified by silica gel
chromatography to give 0.29 g (55%) of the titled compound 32 as a yellow oil; IR (thin
-1 1
film) 3128, 2984, 1790, 1750, 1610, 1426, 1255, 1091, 840, and 762 cm ; H-NMR
(
CDCl , 400 MHz) δ 1.22 (t, 3H, J = 6.8 Hz), 4.10 (s, 2H), 4.21 (q, 2H, J = 6.8 Hz), 5.24
3
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(
d, 1H, J = 0.4 Hz), 5.42 (d, 1H, J = 1.2 Hz), 6.11 (dd, 1H, J = 3.2 and 1.2 Hz), 6.41 (dd,
1
H, J = 3.2 and 2.0 Hz), 7.13 (td, 1H, J = 7.6 and 2.0 Hz), 7.27 (td, 1H, J = 7.2 and 1.2
Hz), 7.33 (dd, 1H, J = 2.0 and 1.2 Hz), 7.40 (dd, 1H, J = 7.6 and 2.0 Hz), and 7.54 (dd,
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
1
3
1
H, J = 8.0 and 1.2 Hz); C-NMR (CDCl , 100 MHz) δ 14.1, 44.5, 63.7, 106.5, 111.4,
3
120.7, 121.7, 127.3, 128.9, 131.6, 132.5, 140.9, 142.3, 142.4, 142.9, 152.8, and 172.0;
+
BrNO ) + H ]: 378.0341. Found: 378.0344.
7 16 4
HRMS Calcd for [(C
H
1
Ethyl 3a-(2-Bromophenyl)-2,5-dioxo-2,3,3a,4,5,6-hexahydro-1H-indole-1-carboxylate
(
34). A solution of the above furanyl carbamate 32 (0.08 g, 0.2 mmol) in toluene (2.5 mL)
o
was heated in a sealed tube at 150 C for 10 h. The reaction mixture was cooled to rt and
concentrated under reduced pressure. The residue was purified by silica gel
chromatography to provide 0.07 g (90%) of the titled compound 34 as a yellow oil; IR
-1 1
(
thin film) 2925, 2982, 1771, 1730, 1680, 1421, 1370, 1293, 1104, and 765 cm ; H-
NMR (CDCl , 400 MHz) δ 1.41 (t, 3H, J = 7.6 Hz), 2.75 (d, 1H, J = 15.2 Hz), 2.84 (dd, 1H,
3
J = 22.8 and 2.8 Hz), 2.98 (d, 1H, J = 18.0 Hz), 3.06 (dd, 1H, J = 22.8 and 5.6 Hz), 3.61
(
d, 1H, J = 18.0 Hz), 3.99 (d, 1H, J = 15.2 Hz), 4.37-4.49 (m, 2H), 6.57 (dd, 1H, J = 5.6
and 2.8 Hz), 7.15 (td, 1H, J = 7.2 and 1.6 Hz), 7.25 (td, 1H, J = 7.6 and 1.6 Hz), 7.38 (dd,
1
3
1H, J = 7.6 and 1.6 Hz), and 7.64 (dd, 1H, J = 7.6 and 1.6 Hz); C-NMR (CDCl , 100
3
MHz) δ 14.4, 38.0, 45.7, 47.9, 49.8, 64.0, 109.0, 122.6, 128.4, 128.9, 130.3, 136.7, 136.8,
+
1
39.7, 151.1, 171.2, and 206.4; HRMS Calcd for [(C
H
BrNO ) + H ]: 378.0341.
17 16
4
Found: 378.0338.
Ethyl 3-(2-Azidophenyl)but-3-enoyl(furan-2-yl)carbamate (33). To a stirred solution of
-(2-bromophenyl)but-3-en-1-ol (0.73 g, 3.2 mmol) in dry DMF (24 mL) was added tert-
3
butyldimethylsilyl chloride (1.07 g, 7.1 mmol) at rt under nitrogen followed by the addition
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of imidazole (0.66 g, 9.7 mmol) and DMAP (8 mg). The mixture was stirred for 2 h at 25
ºC, poured into water and extracted with EtOAc. The organic layer was washed with
water, dried over MgSO and the solvent was removed under reduced pressure. The
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
crude residue was subjected to silica gel column chromatography to yield 1.0 g (91%) of
(
3-(2-bromophenyl)but-3-enyloxy)(tert-butyl)dimethylsilane as a clear oil: IR (neat) 2955,
-
1 1
2
928, 2857 and 1470 cm ; H-NMR (CDCl , 300 MHz) δ 0.01 (s, 6H), 0.87 (s, 9H), 2.67
3
(
t, 2H, J= 7.0 Hz), 3.65 (t, 2H, J= 7.0 Hz), 5.01 (d, 1H, J= 1.5 Hz), 5.26 (d, 1H, J= 1.5 Hz),
1
3
7.09-7.19 (m, 2H), 7.23-7.28 (m, 1H) and 7.54 (dd, 1H, J= 7.9 and 1.2 Hz); C-NMR
(
CDCl , 400 MHz) δ -5.1, 18.5, 26.1, 40.3, 61.7, 117.1, 122.1, 127.2, 128.6, 130.8, 132.8,
3
1
43.9 and 147.2.
A 0.17 g (0.48 mmol) sample of the above compound was dissolved in freshly
distilled THF (5.5 mL) and cooled to -78 ºC. To this mixture was added n-BuLi (27 mL,
1
3
.9 M in hexane, 0.53 mmol) over a 5 min period and the reaction mixture was stirred for
0 min and then tosyl azide (0.19 g, 0.97 mmol) was added in 400 mL of dry THF over 4
min. The solution was stirred at -78 ºC for 1 h and then warmed to rt. After stirring at this
temperature for 45 min, 4 ml of H O was added and the mixture was extracted with
2
CH Cl , dried over MgSO and the solvent was removed under reduced pressure. The
2
2
4
crude residue was subjected to silica gel chromatography to provide 0.14 g (82%) of (3-
2-azidophenyl)but-3-enyloxy)(tert-butyl)dimethylsiline: IR (neat) 2955, 2929, 2857, 2128
(
-
1 1
and 2095 cm ; H-NMR (CDCl , 300 MHz) δ 0.00 (s, 6H), 0.87 (s, 9H), 2.70 (dt, 2H, J=
3
7
7
.0 and 0.6 Hz), 3.62 (t, 2H, J= 7.0 Hz), 5.04 (d, 1H, J= 1.8 Hz), 5.22-5.23 (m, 1H,), 7.07-
1
3
.19 (m, 3H) and 7.29-7.36 (m, 1H); C-NMR (CDCl , 400 MHz) δ -5.2, 18.5, 26.1, 40.2,
3
62.0, 117.1, 118.5, 124.9, 128.7, 130.8, 135.0, 137.0 and 145.1.
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To a stirred solution of the above silyl ether (0.41 g, 1.4 mmol) in dry THF (14 mL)
was added tetra-n-butylammonium fluoride (1.8 mL, 1M in THF, 1.8 mmol) at 25 ºC. After
stirring for 1 h, the solution was taken up in EtOAc, washed with water, dried over MgSO
4
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
and the solvent was removed under reduced pressure. The residue was purified by silica
gel chromatography to provide 0.16 g (76%) of 3-(2-azidophenyl)-but-3-en-1-ol as a clear
-
1 1
oil: IR (neat) 3364, 2937, 2128 and 1487 cm ; H-NMR (CDCl , 400 MHz) δ 1.66 (s,
3
1
H), 2.70-2.73 (m, 2H), 3.61 (t, 2H, J= 6.0 Hz), 5.11 (d, 1H, J=1.6 Hz), 5.32-5.33 (m, 1H),
1
3
7.11-7.20 (m, 3H) and 7.32-7.37 (m, 1H); C-NMR (CDCl , 400 MHz) δ 40.6, 60.4,
3
1
0
18.3, 118.4, 125.0, 128.8, 130.4, 134.2, 137.1 and 144.0.
To a stirred solution of the above alcohol (0.22 g, 1.2 mmol) in acetone (24 mL) at
ºC was added freshly prepared Jones´ reagent (2.4 mL, 2.4 mmol, 1.0 M). The resulting
solution was stirred at 0 ºC for 1 h and the mixture was diluted with water and extracted
with EtOAc. The organic layer was dried over MgSO , filtered and concentrated under
4
reduced pressure. The residue was purified by silica gel chromatography to give 0.2 g
(86%) of 3-(2-azidophenyl)but-3-enoic acid as a yellow solid, mp 73-74 ºC; IR (CH Cl )
2
2
-
1 1
3
080, 2926, 2130 and 1710 cm ; H-NMR (CDCl , 300 MHz) δ 3.58 (d, 2H, J= 0.6 Hz),
3
5.27 (d, 1H, J= 1.2 Hz), 5.38 (d, 1H, J= 1.2 Hz), 7.09-7.16 (m, 2H), 7.25-7.28 (m, 1H) and
1
3
7
.32-7.37 (m, 1H); C-NMR (CDCl , 400 MHz) δ 41.9, 118.4, 120.7, 125.0, 129.2,
3
131.0, 133.2, 137.0, 139.9 and 177.7.
To a stirred solution of ethyl furan-2-ylcarbamate (0.08 mg, 0.51 mmol) in dry THF
(
2.6 ml) cooled to -78 ºC was added n-BuLi (224 mL, 0.56 mmol, 2.5 M in hexane)
dropwise and the reaction mixture was stirred at -78 ºC for 45 min. In a separate flask,
the above azido carboxylic acid (0.12 g, 0.6 mmol) was dissolved in dry THF (4.8 ml) and
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