A copper-catalyzed coupling reaction of vinyl halides and carbazates: Application in the assembly of polysubstituted pyrroles

Article abstract of DOI:10.1039/c3cc49724k

CuI-catalyzed coupling of vinyl halides with carbazates gives N-protected N-alkenylhydrazines, which are condensed with ketones under acidic conditions to give polysubstituted pyrroles. The pyrrole synthesis may go through a similar mechanism with Fischer indole synthesis, which involves a [3,3]-sigmatropic rearrangement and other reactions. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc49724k

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Journal Name
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COMMUNICATION
Copper-Catalyzed Coupling Reaction of Vinyl Halides
and Carbazates: Application in Assembly of
Polysubstituted Pyrroles
Cite this: DOI: 10.1039/x0xx00000x
Chengang Zhou,a,b and Dawei Ma*a,c
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
to afford NꢀBocꢀNꢀalkenylhydrazines.8 Based on our observations in
CuI-catalyzed coupling of vinyl halides with carbazates gives
-protected -alkenylhydrazines, which is condensed with
ketones under acidic conditions to give polysubstituted
pyrroles. The pyrrole synthesis may go through a similar
mechanism with Fischer indole synthesis, which involves a
Cuꢀcatalyzed arylation of carbazates,7f we envisioned that vinylation
of tertꢀbutyl carbazate might occur under the assistance of a copper
catalyst. In the subsequent investigations, we discovered that CuI
alone could catalyze the coupling reaction of vinyl halides with
carbazates (Scheme 1), and the resulting Nꢀprotected Nꢀ
alkenylhydrazines 2 could condense with ketones under acidic
conditions, accompanying with a [3,3]ꢀsigmatropic rearrangement
and other reactions to provide polysubstituted pyrroles 3 and/or 4
with great diversity.9 Herein, we wish to disclose our results.
N
N
[3,3]-sigmatropic rearrangement and other reactions
.
Since it was discovered over a hundred years ago, Fischer indole
synthesis has played an incredible role in the synthesis of natural
products and designed bioactive molecules owing to its convenience,
simplicity and excellent generality.1 Meanwhile, modification of this
transformation by exploring alternative approaches to assemble
required arylhydrazines and arylhydrazones has gained increasing
attention.1,2 However, little attention has been directed to pyrrole
synthesis through
pathway, despite the fact that PilotyꢀRobinson pyrrole synthesis has
been known for about
century.3ꢀ6 Unlike arylhydrazines,
a similar [3,3]ꢀsigmatropic rearrangement
a
unprotected Nꢀalkenylhydrazines are generally unstable, and
therefore the previous PilotyꢀRobinson pyrrole synthesis was limited
to symmetrical azines (prepared in situ from hydrazine and ketones)
as the starting materials. To overcome this drawback, Baldwin and
Bottaro developed a stepwise approach to synthesize unsymmetrical
azines,5 while Buchwald and coworkers designed a sequential Cuꢀ
catalyzed vinylation of bisꢀBocꢀhydrazine to prepare biseneꢀ
hydrazides.6 Although their modifications led to formation of
unsymmetrical pyrroles successfully, a more efficient and general
approach for PilotyꢀRobinson pyrrole synthesis is still desirable to
make this old method more synthetically useful.
During the past years, Pdꢀ or Cuꢀcatalyzed coupling reaction of
aryl halides with tertꢀbutyl carbazate has been intensively studied.
The reaction generally occurred at the NHBoc part to afford the
corresponding arylation products regioselectively.7 In 2007,
Barluenga and coworkers reported that vinyl halides could undergo a
similar coupling reaction under the catalysis of Pd(0) and Johnphos
Scheme 1. Two step pyrrole synthesis from vinyl halides
As shown in Table 1, we started our investigation by conducting a
coupling reaction of βꢀbromostyrene and tertꢀbutyl carbazate. It was
found that under the catalysis of CuI/4ꢀhydroxyꢀLꢀproline,7f this
o
reaction worked at 80 C to give the desired coupling product 2a in
27% yield (entry 1). A much better yield was obtained by changing
ligand to N,Nꢀdimethylglycine (entry 2). Further exploration
revealed that ligand is unnecessary in this coupling reaction
(compare entries 2 and 3), and increase of the catalytic loading of
CuI to 20 mol % gave the highest yield (entry 4). Changing base
from Cs2CO3 to K2CO3 also gave an excellent yield, although a
prolonged reaction time was needed (entry 5). The solvent played an
important role for this coupling reaction. DMF gave a decreased
yield (entry 6), while poor conversions were observed when dioxane
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DOI: 10.1039/C3CC49724K
and toluene were employed (entries 7 and 8). The employment of a
strong base and
With a convenient method for assembling protected Nꢀalkenylꢀ
polar solvent could have facilitated the hydrazines 2 in hand, we next moved our attention to pyrrole
a
deprotonation of the NHBoc moiety. These results indicated that use synthesis by reacting 2 with ketones. Gratifyingly, when NꢀBocꢀNꢀ
of CuI as the catalyst, Cs2CO3 as the base and DMSO as the solvent alkenylhydrazine 2g and cyclohexanone was treated with H2SO4 in
is the best combination for vinylation of tertꢀbutyl carbazate.
refluxed ethanol, the desired pyrrole 3a was isolated in 75% yield
We next explored the reaction scope by varying protecting (Table 2, entry 1). Under MW irradiation, a better yield was
hydrazines and vinyl halides. Like tertꢀbutyl carbazate, benzyl observed (entry 2). Good yields were also observed in the reaction of
carbazate and ethyl carbazate were suitable coupling partners for
reacting with (E)ꢀ1ꢀ(2ꢀbromovinyl)ꢀ4ꢀmethylbenzene, giving the
corresponding vinylation products 2bꢀ2d in excellent yields (entries
9ꢀ11). The electronic nature in aromatic ring has little influence to
this reaction, as similar yields were observed for both electronꢀrich
and electronꢀdeficient βꢀbromostyrenes (entries 12ꢀ19). When (E)ꢀ1ꢀ
bromoꢀ4ꢀ(2ꢀbromovinyl)benzene was employed, coupling reaction
took place regioselectively to give 2l in 67% yield (entry 19),
presumably because vinyl bromide part was more reactive than aryl
bromide site toward CuIꢀcatalyzed oxidative addition.
cyclohexanone with other βꢀaryl substituted Nꢀalkenylhydrazines
(entries 3ꢀ7). When cycloheptanone was used, pyrrole 3g was
isolated in 46% yield (entry 8). Additionally, some acyclic ketones
were all applicable, providing 1,2,3,4ꢀtetrasubstituted pyrroles 3hꢀ3k
in 51ꢀ84% yields (entries 9ꢀ12).
Table 2. Pyrrole synthesis from Nꢀprotected Nꢀalkenylhydrazines
and ketones under acidic conditionsa
Table 1. CuIꢀcatalyzed vinylation of carbazatesa
entry
1c
product/yieldb
entry
8c
product/yieldb
R/R'
X
Y
t
(h)
24
24
24
2
15
25
24
24
2
2
2
2
2
2
2
2
2
product
(yield (%))b
2a (27)c
2a (73)d
2a (76)
2a (92)
2a (92)e
2a (72)f
2a (5)g
entry
H/Ph
H/Ph
H/Ph
H/Ph
H/Ph
H/Ph
H/Ph
H/Ph
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
CO2Et
Boc
Cbz
Boc
Cbz
Boc
Cbz
Boc
Boc
Boc
Cbz
Boc
Cbz
Boc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3g: X = 4ꢀOMe, 46%
3a: X = 4ꢀOMe, 75%
3a: X = 4ꢀOMe, 80%
2d
3d
4d
9c
3b: X = 4ꢀMe, 79%
2a (5)h
H/4ꢀMeC6H4
H/4ꢀMeC6H4
H/4ꢀMeC6H4
H/3,4ꢀ(MeO)2C6H3
H/4ꢀMeOC6H4
H/4ꢀMeOC6H4
H/4ꢀFC6H4
H/4ꢀFC6H4
H/4ꢀClC6H4
H/4ꢀClC6H4
H/4ꢀBrC6H4
Ph/Ph
2b (90)
2c (90)
2d (91)
2e (89)
2f (89)
2g (91)
2h (85)
2i (83)
2j (85)
2k (86)
2l (68)
2m (72)
2n (75)
2o (85)
2p (89)
2q (85)
3h: Y = 4ꢀMeOC6H4,
84%
3i: Y = 4ꢀMeC6H4, 66%
3c: X = 4ꢀOMe, 86%
3d: X = 4ꢀMe, 82%
5d
6c
7c
10c
11c
12c
3e: X = 4ꢀF, 74%
3f: X = 4ꢀCl, 69%
3j: Y = 4ꢀFC6H4, 56%
3k: Y = Me, 51%
aAlkenylhydrazine 2 (1 mmol), ketone (1.2 mmol), H2SO4 (2 mmol, for entries 1ꢀ
10) or TsOH (2 mmol, for entries 11 and 12), EtOH (8 mL). bIsolated yield.
cReflux for 2ꢀ4 h. dMW irradiation for 10 min at 100 oC.
2
2
2
2
4
4
4
Ph/Ph
I
I
I
I
nꢀPr/nꢀPr
nꢀPr/nꢀPr
2ꢀthiophenyl/
(CH2)3CN
4ꢀMeOC6H4/
2ꢀCNC6H4
(CH2)4
I
Boc
4
2r (73)
25
I
Boc
4
2s (70)
26
aVinyl halide (1 mmol), H2NNHY (1.2 mmol), CuI (0.1 mol for entries 1ꢀ3, 0.2
mmol for entries 4ꢀ26), Cs2CO3 (1.4 mmol), DMSO (2 mL), 80 oC. bIsolated yield.
c0.2 mmol of 4ꢀhydroxyꢀLꢀproline was added. d0.2 mmol of N,Nꢀdimethylglycine
was added. eK2CO3 was used as the base. fDMF was used as the solvent. gDioxane
was used as the solvent. hToluene was used as the solvent.
Further explorations demonstrated that some trisubstituted vinyl
iodides were compatible with the reaction conditions, leading to
formation of α,βꢀdisubstituted alkenylhydrazines 2mꢀ2s in good
yields (entries 20ꢀ26). Noteworthy is that α,βꢀdiaryl (entries 20, 21
and 25), α,βꢀdialkyl (entries 22 and 23), αꢀarylꢀβꢀalkyl (entry 24)
substituted vinyl iodides and a cyclic vinyl iodide (entry 26) were
applicable, thereby allowing diverse synthesis of protected Nꢀ
alkenylhydrazines.
Scheme 2. Preparation of 2,3,4,5ꢀtetrasubstituted and fully substituted
pyrroles and imine intermediate 5a
Fully substituted pyrroles 3l and 3m could be obtained if α,βꢀ
disubstituted alkenylhydrazines were used (Scheme 2). Interestingly,
in this case the corresponding deprotection products 4a and 4b were
also isolated. In order to identify how these products formed, we
2 | J. Name., 2012, 00, 1-3
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DOI: 1C0.O10M39M/CU3CNCI4C9A72T4IOK N
carefully checked the side products, and found that aminal 5a could alkenylhydrazines could deliver 2,3,4ꢀtrisubstituted pyrroles in
be obtained from the reaction of the alkenylhydrazine 2p with 1ꢀ(4ꢀ
methoxyphenyl)propanꢀ2ꢀone. Heating 5a in HOAc/EtOH at reflux
produced 4b in 85% yield. In contrast, transformation of 3m to 4b
was found impossible under the same conditions or by treating 3m
with H2SO4 in refluxed EtOH. These results clearly indicated that 4b
should result from the elimination of the aminal 5a, but not from the
direct deprotection of 3m.
Based on our experimental observations and established
mechanism for Fischer indole synthesis,1 we believed that the
present pyrrole synthesis might go through a process outlined in
Scheme 3. Condensation of 2 with ketones under acidic conditions
produced alkenylhydrazones 6, which would undergo isomerization
to give the respective enehydrazides 7. After protonation, a cyclic
[3,3]ꢀsigmatropic rearrangement might occur to provide iminiums 8.
Finally, cyclization of 8 produced aminals 5, which would furnish
energetically favorable aromatic molecules 4 via elimination and
isomerization (pathway a). Alternatively, the iminiums 8 might give
olefins 9 upon isomerization. Condensative cyclization of 9 and
satisfactory yields, while corresponding βꢀalkyl substituted NꢀCbzꢀ
Nꢀalkenylhydrazines did not produce the corresponding pyrroles
under the same conditions (data not shown); 3) this cascade reaction
process tolerates a wide range of functional groups such as
carboxylic acid, hydroxyl, olefin, halogens, nitro, thiophenyl and
pyridinyl group on both condensation partners; 4) some known
building blocks for assembling bioactive and material molecules
could be obtained using this method. For example, 2,3,4ꢀ
trisubstituted pyrroles 4w and 4x have been applied in the synthesis
of HMGꢀCoA reductase inhibitors,10 pyridineꢀembodied pyrrole 4y
has been employed for preparing a promising agent for the treatment
of disorders ameliorated by reduction of TNFꢀα production and/or
p38 activity,11 2,3,4ꢀtrisubstituted pyrroles 4z and 4ab could be used
for assembling Bclꢀ2 and BclꢀxL inhibitors,12 the corresponding
esters of substituted pyrroles 4ad and 4ae have been utilized for the
total synthesis of some marine alkaloids13 like lukianol A,14 ningalin
B15 and lameellarin O,14a while ethyl ester of 4ae is the intermediate
for constructing 2,2’ꢀbipyrrole that exhibited strong blue
fluorescence.16
subsequent elimination could afford 1ꢀsubstituted pyrroles
3
(pathway b). Obviously, formation of the intermediates 5 and 9
should depend on the nature of substrates 8 and the reaction
conditions.
Table 3. Reaction of protected Nꢀalkenylhydrazines with αꢀketo
acida
F
Br
MeO
R
R
CO2H
N
H
CO2H
CO2H
N
H
N
H
4v: R =
i-Pr, 66%
4w: R = Ph, 79%
4x: R = 4-FC6H4, 78%
4y: R = 4-pyridyl, 65%
4ac, 79%
4c: R = Me, 78%
4d: R = Et, 77%
4e: R = i-Pr, 69%
4f: R = CH2CO2H, 72%
4g: R = CH2CH2OH, 46%
4h: R = (CH2)2CH=CH2, 69%
4i: R = Ph, 82%
Cl
Me
OMe
4j: R = 4-FC6H4, 73%
4k: R = 4-ClC6H4, 75%
4l: R = 4-BrC6H4, 74%
4m: R = 4-MeC6H4, 80%
4n: R = 4-HOC6H4, 71%
4o: R = 4-MeOC6H4, 83%
4p: R = 4-O2NC6H4, 83%
4q: R = 4-CF3C6H4, 73%
4r: R = 3-BrC6H4, 79%
4s: R = 2-O2NC6H4, 75%
4t: R = 2-thiophenyl, 72%
4u: R = 4-pyridyl, 68%
R
Scheme 3. Possible reaction process for pyrrole formation from
protected Nꢀalkenylꢀhydrazines and ketones.
CO2H
N
H
CO2H
N
H
The 2ꢀcarboxyl pyrrole moiety has been found in a great number
of natural products and designed bioactive molecules.10ꢀ15 To check
if the present method could be applied for assembling 2ꢀcarboxyl
pyrroles, we investigated the condensation reaction of NꢀCbzꢀNꢀ
alkenylhydrazine 2f with αꢀketo acids. To our delight, HOAcꢀ
mediated reaction of 2f with 2ꢀoxobutanoic acid proceeded smoothly
in ethanol at 70 oC to provide pyrrole 4c in 78% yield (Table 3). No
corresponding 1ꢀCbz pyrrole was determined, indicating that the
reaction goes through the “pathway a” (Scheme 3) exclusively.
Using 2f as a condensation partner, we examined a variety of αꢀ
keto acids to explore the reaction scope. It was found that both
aliphatic and aromatic αꢀketo acids performed well, resulting in
2,3,4ꢀtrisubstituted pyrroles 4dꢀ4u in 46ꢀ83% yields. Variation of the
NꢀCbzꢀNꢀalkenylhydrazine partner was possible, as evident from that
trisubstituted pyrroles 4vꢀ4ae were constructed in good yields.
Notable features of this transformation include: 1) by employing
suitable αꢀketo acids, a large number of substituents could be
introduced into the 3ꢀposition of 2ꢀcarboxyl pyrroles, which include
simple and functionalized alkyl groups, as well as substituted aryl
groups and heteroaryl groups; 2) only βꢀaryl substituted NꢀCbzꢀNꢀ
4z: R = Ph, 79%
4aa: R = 4-ClC6H4, 78%
4ab: R = 3-BrC6H4, 71%
4ad, 78%
MeO
MeO
OMe
OMe
NC
CO2H
N
H
CO2H
N
H
S
CO2H
N
H
4ag, 70%
4af, 73%
MeO
4ae, 77%
NC
Me
Me
CN
CO2H
4ah, 50%
N
H
CO2H
N
H
S
4ai, 68%
aThe protected Nꢀalkenylhydrazine (1 mmol), αꢀketo acid (1 mmol), HOAc (5
mmol), EtOH (8 mL), 70ꢀ90 oC, 1.5ꢀ16 h.
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Further studies demonstrated that 2,3,4,5ꢀtetrasubstituted pyrroles
4afꢀ4ai could be synthesized by using α,βꢀdiaryl or αꢀarylꢀβꢀalkyl
substituted NꢀCbzꢀNꢀalkenylhydrazines as the condensation partners.
In this case introducing alkyl groups at the 3ꢀposition of the 2ꢀ
carboxyl pyrroles was possible, as 4ag and 4ah being isolated in
reasonable yields.
8
9
J. Barluenga, P. Moriel, F. Aznar, C. Valdés, Org. Lett. 2007, 9, 275.
For recent reports on pyrrole synthesis, see: (a) M. Gao, C. He, H. Chen,
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Conclusions
In conclusion, we have developed a twoꢀstep pyrrole synthesis
starting from vinyl halides, which relies on a copperꢀcatalyzed
vinylation of carbazates and an acidꢀmediated cascade reaction
process like Fischer indole synthesis. The scope of this method
is quite satisfactory, as demonstrated by the easy access to a
variety of 2,3,4ꢀtrisubstituted, 1,2,3,4ꢀtetrasubstituted, 2,3,4,5ꢀ
tetrasubstituted and fully substituted pyrroles. By employing
suitable condensation partners, a large number of substituents
could be installed into the pyrrole ring system in
a
regiocontrolled and efficient fashion. The simplicity and good
generality displayed by this method will make it as a
competitive approach for preparing pyrroleꢀcontaining
bioactive and material molecules. Detailed mechanistic studies
and further explorations on reaction scope are in progress.
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aSchool of Pharmacy, East China University of Science and Technology,
130 Meilong Lu, Shanghai 200037, China
bRoche Pharma Research & Early Development (pRED) China, 720
Cailun Road, Shanghai 201203, China
cState Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China. Fax: 86ꢀ21ꢀ64166128; Tel: 86ꢀ
21ꢀ54925130; Eꢀmail: madw@mail.sioc.ac.cn.
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