[3+2]Cycloaddition of propargylamines and α-acylketene dithioacetals: A synthetic strategy for highly substituted pyrroles

Article abstract of DOI:10.1002/adsc.201200375

A new [3+2] cycloaddition strategy for the direct synthesis of highly substituted pyrroles from the readily available α-acylketene dithioacetals (or related substrates) and commercially available propargylamines under mild metal-free conditions has been developed. In this reaction, the acyl group plays a critical role in driving the conjugate addition of propargylamine and further cyclization to give pyrroles. Furthermore, the wide scope was confirmed by the preparation of 1,2,3,4-tetrasubstituted pyrroles (60-70% yields) via a formal 1,2-acyl migrating [3+2] cycloaddition pathway with N-methylprop-2-yn-1-amine as the secondary amine component.

Full text of DOI:10.1002/adsc.201200375

FULL PAPERS
DOI: 10.1002/adsc.201200375
[3+2]Cycloaddition of Propargylamines and a-Acylketene
Dithioacetals: A Synthetic Strategy for Highly Substituted
Pyrroles
Yu-Long Zhao,a,* Chong-Hui Di,a Si-Di Liu,a Jia Meng,a and Qun Liua,*
a
Department of Chemistry, Northeast Normal University, Changchun 130024, Peopleꢀs Republic of China
Fax : (+86)-431-8509-9759; e-mail: zhaoyl351@nenu.edu.cn or liuqun@nenu.edu.cn
Received: April 29, 2012; Revised: August 16, 2012; Published online: December 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200375.
Abstract: A new [3+2]cycloaddition strategy for the by the preparation of 1,2,3,4-tetrasubstituted pyrroles
direct synthesis of highly substituted pyrroles from (60–70% yields) via a formal 1,2-acyl migrating [3+
the readily available a-acylketene dithioacetals (or 2]cycloaddition pathway with N-methylprop-2-yn-1-
related substrates) and commercially available prop- amine as the secondary amine component.
argylamines under mild metal-free conditions has
been developed. In this reaction, the acyl group
plays a critical role in driving the conjugate addition Keywords:
of propargylamine and further cyclization to give [3+2]cycloaddition; propargylamines; pyrroles; syn-
pyrroles. Furthermore, the wide scope was confirmed thetic methods
a-acylketene
dithioacetals;
AHCTUNGTRENNUNG
Introduction
paper, we report our results regarding this new [3+
2]cycloaddition strategy (Scheme 1) and the synthesis
Functionalized ketene dithioacetals are versatile inter- of highly substituted pyrroles 7 in a single step from
mediates in organic synthesis.[1,2] Recently, several re- reactions of readily available starting materials 1 with
À
ports were published highlighting the C C bond for- primary propargylamines 3 under mild transition
mation at the a-carbon of a-EWG ketene dithioace- metal-free conditions and the extension of this meth-
tals 2 (EWG=electron-withdrawing group) and their odology.
applications in heterocyclic synthesis.[3] In these reac-
tions, a-EWG ketene dithioacetals 2 were prepared
by a two-step process involving, for example, the
preparation of the a-acetylketene dithioacetals 1 start-
ing from the corresponding active methylene com-
pounds, carbon disulfide and alkyl halides in the pres-
ence of K2CO3 catalyzed by tetrabutylammonium bro-
mide (TBAB) in water,[4] followed by acid/base-pro-
moted deacylation (Scheme 1).[3e] In this context, we
envisioned that an efficient route to 2,3,4-trisubstitut-
ed pyrroles 7 could be possible from the reaction of
primary propargylamines 3 and a-acetylketene di-
thioacetals 1 in the presence of a suitable base. Ac-
cording to Scheme 1, this synthetic strategy would in-
volve (i) the selective formation of N,S-acetal inter-
mediate 4 from acetyl enhanced addition-elimination
(SNV) of propargylamine 3 to 1;[1,2c–e] (ii) in situ gener-
ation of intermediate 6 via a sequential tautomeriza-
tion and 5-exo-dig cyclization; and ultimately (iii) the
formation of 2,3,4-trisubstituted pyrroles 7 from 6 via
deacylation and subsequent isomerization.[5] In this Scheme 1. Proposed synthesis of 2,3,4-trisubstituted pyrroles.
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Although the synthesis of pyrroles has been an im-
portant subject for more than a century,[6] new and
straightforward methods to access these compounds
from simple starting materials are still highly desira-
ble due to their potential in pharmaceutical and other
value added areas.[7–9] For example, the methods uti-
lize alkynes[7] including N-Boc-protected propargyl-
Scheme 2.
ACHTUNGTRENNUNGamines as starting materials in the presence of Pd cat-
alysts.[8] In addition, an InBr3-Et3N-catalyzed formal dependent. Interestingly, under identical conditions
[3+2]cycloaddition of primary propargylamine with but in the absence of an external base, 7a was pro-
2-tert-butyl 1,1-diethyl ethene-1,1,2-tricarboxylate to duced in higher yield (Table 1, entry 5). To our de-
give the corresponding methylenepyrrolidine was also light, the yield of 7a rose to 97% by increasing the
reported.[9] To the best of our knowledge, however, amount of 3a to 2.0 equivalents without the addition
no previous work has reported the one-pot synthesis of an external base (Table 1, entry 6). In comparison,
of pyrroles directly from primary propargylamines.[6–8] no 7a was detectable on treating 2a with 3a
(2.0 equiv.) in DMF either in the presence or absence
of K2CO3 (1.0 equiv.), even at higher temperature
Results and Discussion
(1208C, Scheme 2). This result indicates that 2a would
not be involved in the formation of 7a (see Scheme 1)
Indeed, the reaction of a,a-diacetylketene dithioace- since 2a (having one EWG) is much less reactive than
tal 1a with propargylamine 3a supported the reliabili- 1a (having two EWGs) for the SNV reaction.[1] On the
ty of the proposed procedure (see Scheme 1). Howev- other hand, this result also means that the acyl group
er, in the presence of K2CO3 or DBU (1,8- of substrates 1 is important to enhance the conjugate
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene), the desired product addition pathway (Scheme 2 versus Scheme 3). The
2,3,4-trisubstituted pyrrole 7a was produced only in solvent effect was also investigated. Among the sol-
low to moderate yields (25–60%) by treating 1a vents tested, DMF was the best choice (Table 1,
(1.0 mmol) with 3a (1.0 mmol) in DMF (5 mL) at entry 6). Other solvents, such as THF, CH2Cl2 and
608C for 12–16 h (Table 1, entries 1–4). In these cases, CH3CN, gave lower product yields (Table 1, entries 7–
the deacylative product 2a was also obtained and the 9) at reflux temperature).
yield of 2a increased with increasing amount of
To the best of our knowledge, the above procedure
(Table 1, entry 6) represents the first direct synthesis
base.[3e,10]
The above results (Table 1, entries 1–4) indicate of pyrroles with propargylamines as the starting mate-
that the competition between deacylation and acetyl rials.[6–8] In addition, this procedure has the advantage
enhanced addition-elimination (SNV) of propargyl- of allowing the construction of highly substituted pyr-
ACHTUNGTRENNUNGamine 3 to 1 (Scheme 1) seems significantly basicity roles from easily available substrates under mild tran-
Table 1. Optimization of reaction conditions.[a]
Entry
3a (equiv.)
Base (equiv.)
Solvent
Time [h]
Yield [%][b]
7a
2a
1
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
DBU (1.0)
DBU (0.3)
DBU (0.5)
K2CO3 (1.0)
–
–
–
–
–
DMF
DMF
DMF
DMF
DMF
DMF
THF
12
16
12
12
12
12
20
18
20
25
60
54
35
67
97
42
41
28
65
27
30
56
0
0
0
0
0
0
0
0
0
23
0
47
45
63
MeCN
CH2Cl2
[a]
All reactions were carried out in open air.
Isolated yield.
[b]
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ACHTUNGTRENNUNG[3+2]Cycloaddition of Propargylamines and a-Acylketene Dithioacetals
pyrroles 7 accomplished by chemoselective deacyla-
tion.[1,2a,3e]
Furthermore, it was found that the deacylative [3+
2]cycloaddition is sensitive to the nature of the EWG
of substrates 1. Under identical conditions as above
(Table 2), the reaction of ethyl 2-[bis(ethylthio)methy-
lene]-3-oxobutanoate 1k (1.0 mmol, EWG=EtOCO)
with propargylamine 3a (2.0 equiv.) for 4 h did not
give the desired 2,3,4-trisubstituted pyrrole 7k, but
the double addition-elimination product, ketene N,N-
acetal 8, in 90% yield (Scheme 3).[1] In comparison, 8
and ketene N,S-acetal 4k were obtained in 53 and
40% yields, respectively, from the reaction of 1k
(2.0 mmol) with 3a (1.0 mmol) for 3 h (Scheme 3). In
addition, it was observed that the desired product 7k
could be obtained in 90% yield by treatment of 4k
(1.0 mmol) with K2CO3 (1.0 equiv.) in DMF (5 mL) at
608C for 8 h (Scheme 3). Thus, after optimization of
the reaction conditions, 7k was prepared in 91% yield
Scheme 3.
sition metal-free conditions in a single step. With from the reaction of 1k (1.0 mmol) with 3a
a viable protocol in hand, the scope of the reaction (1.0 equiv.) in the presence of K2CO3 (1.0 equiv.) in
was then investigated with propargylamine 3a and the DMF (5 mL) at 608C for 12 h (Scheme 3). Clearly,
corresponding a-acylketene dithioacetals 1 (Table 2). the transformation from 4k to 7k supports the pro-
It was observed that all the reactions of 3a with acyl- posed mechanism for the synthesis of 2,3,4-trisubsti-
ketene dithioacetals 1a-j bearing as the EWG acetyl tuted pyrroles 7 as described in Scheme 1, namely, the
(Table 2, entry 1), propionyl (Table 2, entry 2), N-aryl- [3+2]cycloaddition reaction. By the reaction of 1k
carbamoyl with either electron-rich (Table 2, en- with 3a, an ethoxycarbonyl group was introduced re-
tries 5–9), electron-neutral (Table 2, entry 3) or elec- giospecifically in the 3-position of 7k.
tron–deficient groups (Table 2, entries 4 and 10) on
Furthermore, 2,3,4-trisubstituted pyrroles 7l (from
the benzyl ring, can afford the desired 2,3,4-trisubsti- 1l and 3a), 7m (from 1m and 3a), 7n (from 1a and
tuted pyrroles 7a–j in high to excellent yields. These 3b),[11] 7o (from 1n and 3a) and 7p (from 1o and 3a)
results mean that an acetyl (Table 2, entry 1), pro- were also prepared in high to excellent yields under
pionyl (Table 2, entry 2) and various N-arylcarbamoyl optimal conditions (Table 3). These results showed
groups (Table 2, entries 3–10) can be introduced re- that a meth/ethoxycarbonyl (Table 3, entry 1, also see
giospecifically in the 3-position of 2,3,4-trisubstituted Scheme 3), benzoyl (Table 3, entry 2), cyano (Table 3,
Table 2. Synthesis of 2,3,4-trisubstituted pyrroles 7a–j from 1a–j and 3a.[a]
Entry
1
R
EWG
Time [h]
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Et
MeCO
EtCO
C6H5NHCO
4-ClC6H4NHCO
4-MeOC6H4NHCO
2-MeOC6H4NHCO
4-MeC6H4NHCO
2-MeC6H4NHCO
2,4-Me2C6H3NHCO
2-ClC6H4NHCO
12
12
18
16
20
20
18
18
20
18
7a
7b
7c
7d
7e
7f
7g
7h
7i
97
93
91
95
90
88
90
92
89
94
Me
Me
Me
Me
Me
Me
Me
Me
10
1j
7j
[a]
Reaction conditions: 1 (1.0 mmol), 3a (2.0 mmol), DMF (5 mL), 608C, 12–20 h.
Isolated yield.
[b]
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Table 3. Synthesis of 2,3,4-trisubstituted pyrroles 7l–p.[a]
Entry 1
R
EWG R1 Time
[h]
Product Yield
[%][b]
1
2
1l Et CO2Me H 12
1m Ph PhCO 24
1a Me MeCO Ph 16
7l
94
89
70
72
91
H
7m
7n
7o
7p
3
4[c]
5
1n Me CN
1o Me NO2
H
H
10
3
[a]
Reaction conditions: 1 (1.0 mmol), 3 (1.0 or 2.0 mmol),
K2CO3 (1.0 or 2.0 equiv.), DMF (5.0 mL), 608C, 3–24 h.
Isolated yield.
[b]
[c]
2.0 equiv. Cs2CO3 were used.
entry 4) and nitro group (Table 3, entry 5) could also
be introduced regiospecifically in the 3-position of
2,3,4-trisubstituted pyrroles 7, efficiently. In addition,
the successful synthesis of 7n (Table 3, entry 3) could
make the [3+2]cycloaddition reaction applicable to
a wide variety of 2,3,4-trisubstituted pyrroles bearing
different substituents in the 4-position.
To further extend the scope of the [3+2]cycloaddi-
tion reaction, the reactions of propargylamine 3a with
Scheme 5. Synthesis of 1,2,3,4-tetrasubstituted pyrroles 10.
selected
3-[ethylthioACTHNGUTERN(UNG aryl)methylene]pentane-2,4-
diones 9[12] were then examined. As the results, 2,3,4-
trisubstituted pyrroles 7q–s were prepared in high 10a having a acetyl group at the C-2 of the pyrrole
yield from the reaction of 3a (2.0 mmol) with the cor- core could be obtained in 68% yield from 1a
responding 9 (1.0 mmol) in DMF at 608C in the ab- (1.0 mmol) and 3c (2.0 equiv.) in the mixed solvents
sence of base (Scheme 4). These results offer further of water (1.0 mL) and DMF (4.0 mL) in the presence
enhancement of the efficiency of the [3+2]cycloaddi- of K2CO3 (0.5 equiv.) at 808C for 12 h (Scheme 5,
tion reaction.
Conditions D). In this case, the deacylative product
Finally, the reaction of a-acylketene dithioacetals 2a was also obtained in 25% yield. Under identical
with N-methylprop-2-yn-1-amine 3c as the secondary conditions, but in the absence of K2CO3, no reaction
amine component was examined. However, no reac- occurred (Scheme 5, Conditions C). In comparison, 2a
tion between 1a (1.0 mmol) and 3c (2.0 equiv.) was was obtained in 92% yield when the above reaction
observed by treating them in DMF (5 mL) at 808C was performed in DMF at 808C for 8 h in the pres-
for 16 h (Scheme 5, Conditions A, also see Table 1, ence of K2CO3 or Cs2CO3 (0.5 equiv.) (Scheme 5,
entry 6). Detailed examination of the reaction condi- Conditions B; see also Table 1, entry 4).
tions indicated that 1,2,3,4-tetrasubstituted pyrrole
Under the optimal conditions (Scheme 5, Condi-
tions D), the corresponding 1,2,3,4-tetrasubstituted
pyrroles 10b, 10k, 10m, 10p and 10q having two car-
bonyl groups on the C-2 and C-3 atoms were synthe-
sized in good to high yields from reactions of 3c with
1b, 1k, 1m, 1p and 1q, respectively (Scheme 5).[13] The
above reaction provides an easy route to 1,2,3,4-tetra-
substituted pyrroles in a single step from easily avail-
able starting materials although more details for the
actual transport pathway of the 1,2-acyl migrating
[3+2]cycloaddition remain to be clarified.[14] In the
rearrangement, the migration ability of the acetyl
group over ethoxycarbonyl and benzoyl groups was
Scheme 4. Synthesis of 2,3,4-trisubstituted pyrroles 7q–s.
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ACHTUNGTRENNUNG[3+2]Cycloaddition of Propargylamines and a-Acylketene Dithioacetals
2-yn-1-amine as the secondary amine component. Fur-
ther studies are in progress.
Experimental Section
General Methods
All reagents were commercial and were used without fur-
ther purification. Chromatography was carried on flash
silica gel (300–400 mesh). All reactions were monitored by
TLC, which was performed on precoated aluminum sheets
of silica gel 60 (F254). Melting points are uncorrected.
Scheme 6. Proposed mechanism for formation of 10.
1
Unless noted, the H NMR spectra were recorded at 500 or
600 MHz in CDCl3 and the 13C NMR spectra were recorded
at 125 or 150 MHz in CDCl3 with TMS as internal standard.
All coupling constants (J values) are reported in Hertz
(Hz). High-resolution mass spectra (HR-MS) were obtained
using a Bruker microTOF II focus spectrometer (ESI).
observed (for the long-range CH-COSY spectra of
10k, 10p and 10q, see the Supporting Information).
Significantly, different from the [3+2]cycloaddition
of a-acylketene dithioacetals 1 with primary propar-
gylamines 3a or 3b (Table 2) and related mechanisms
(Scheme 1), the synthesis of 1,2,3,4-tetrasubstituted
pyrroles 10 involves an interesting 1,2-rearrangement.
On the basis of the above experimental results togeth-
er with the related reports,[15] a plausible mechanism
for the formation of 10 is proposed in Scheme 6 (with
the reaction of 1a with 3c as an example). The reac-
tion starts from the intermolecular Michael addition
of N-methylprop-2-yn-1-amine 3c to a-acetylketene
dithioacetal 1a to give the intermediate 11.[15] Subse-
General Procedure for the Synthesis of 7 (7a as
example)
To a solution of a-diacetylketene dithioacetal 1a (1.0 mmol,
232 mg) in DMF (5.0 mL) was added prop-2-yn-1-amine 3a
(2.0 mmol, 0.14 mL) in one portion. The reaction mixture
was heated to 608C for 12 h. After 1a had been consumed
(monitored by TLC), the reaction mixture was poured into
water (50 mL) and extracted with CH2Cl2 (10 mLꢂ3). The
combined organic extracts were dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure to
quently, the methylenepyrrolidine intermediate 12, yield the corresponding crude product, which was purified
by silica gel chromatography (acetone/hexane=1/10, v/v) to
give 7a as a white solid; yield: 178 mg (97%); mp 143–
1458C. H NMR (CDCl3, 500 MHz): d=1.24 (t, J=7.5 Hz,
3H), 2.27 (s, 3H), 2.64 (s, 3H), 2.81 (q, J=7.5 Hz, 2H), 6.57
(s, 1H), 8.32 (s, 1H); 13C NMR (CDCl3, 125 MHz): d=13.3,
14.8, 30.4, 30.8, 118.6, 122.7, 126.2, 126.6, 196.0; HR-MS
(ESI-TOF): m/z=206.0608, calcd. for C9H13NNaOS+ ([M+
Na]+): 206.0610.
generated via an intramolecular 5-exo-dig cyclization
reaction of intermediate 11, undergoes a sequential
1,2-acetyl migration and elimination of one ethylthio
group to give the intermediate 13. Finally, 1,2,3,4-tet-
rasubstituted pyrrole 10a is produced via elimination
of the second ethylthio group and aromatization
(Scheme 6).
1
Conclusions
General Procedure for the Synthesis of 10 (10a as
example)
In conclusion, a new [3+2]cycloaddition strategy for
the direct synthesis of 2,3,4-trisubstituted pyrroles has
been developed. By this strategy, a wide range of
2,3,4-trisubstituted pyrroles having various EWG
group at the 3-position were synthesized in high to ex-
To
a solution of a,a-diacetyl ketene dithioacetal 1a
(1.0 mmol, 232 mg) and N-methylprop-2-yn-1-amine 3c
(2.0 mmol, 0.17 mL) in DMF-H2O (5.0 mL, 4:1) was added
K2CO3 (0.5 mmol, 69 mg) in one portion. The reaction mix-
ture was heated to 808C for 12 h. After 1a had been con-
cellent yield (70–97%) from the reactions of the read- sumed (monitored by TLC), the reaction mixture was
poured into water (50 mL) and extracted with CH2Cl2
(10 mL ꢂ 3). The combined organic extracts were dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure to yield the corresponding crude product, which
was purified by silica gel chromatography (acetone/hexane=
1/15, v/v) to give 10a as a white solid; yield: 122 mg (68%);
ily available a-acylketene dithioacetals (or related
substrates) with commercially available primary prop-
argylamines in a single step under mild transition
metal-free conditions. In this reaction, the acyl group
of the substrates plays a critical role in driving the
conjugate addition thus enabling further cyclization to
give pyrroles. Furthermore, the wide scope was con-
firmed by the preparation of 1,2,3,4-tetrasubstituted
pyrroles (60–70% yields) via a formal 1,2-acyl migrat-
1
mp 83–858C. H NMR (CDCl3, 500 MHz): d=2.16 (s, 3H),
2.39 (s, 3H), 2.52 (s, 3H), 3.72 (s, 3H), 6.47 (s, 1H);
13C NMR (CDCl3, 125 MHz): d=11.6, 30.1, 31.7, 36.7, 117.5,
126.9, 130.7, 131.5, 192.5, 199.3; HR-MS (ESI-TOF): m/z=
+
ing [3+2]cycloaddition pathway with N-methylprop- 180.1018, calcd. for C10H14NO2 ([M + H]+): 180.1019.
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Yu-Long Zhao et al.
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A. M. van Leusen, Org. React. 2001, 57, 417 (Van
Leusen pyrrole synthesis: cyclization between a Michael
acceptor and tosylmethyl isocyanide).
Acknowledgements
Financial support of this research by the National Natural
Sciences Foundation of China (20972026 and 21172032) is
greatly acknowledged.
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ˇ
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3550
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Adv. Synth. Catal. 2012, 354, 3545 – 3550