Synergistic rhodium(II) carboxylate and Bronsted acid catalyzed multicomponent reactions of enalcarbenoids: Direct synthesis of α-pyrrolylbenzylamines

Article abstract of DOI:10.1021/ol501508f

The design of a synergistic rhodium(II) carboxylate and BINOL phosphoric acid catalyzed efficient multicomponent reaction of enaldiazo compounds, arylamines, and aryl aldehydes leading to the first transition-metal-catalyzed direct synthesis of valuable α-pyrrolylbenzylamines is disclosed. The reaction is proposed to involve a transient ammonium ylide of a new class of electrophilic rhodium enalcarbenoid, its regioselective Mannich reaction, and a cyclocondensation cascade. The methodology was used in a highly diastereoselective synthesis of a binaphthyl based chiral pyrrole.

Full text of DOI:10.1021/ol501508f

Letter
pubs.acs.org/OrgLett
Synergistic Rhodium(II) Carboxylate and Brønsted Acid Catalyzed
Multicomponent Reactions of Enalcarbenoids: Direct Synthesis of
α‑Pyrrolylbenzylamines
Sudam Ganpat Dawande, Vinaykumar Kanchupalli, Bapurao Sudam Lad, Jyoti Rai,
and Sreenivas Katukojvala*
Department of Chemistry, Indian Institute of Science Education & Research, Bhopal, Madhya Pradesh 462066, India
S
* Supporting Information
ABSTRACT: The design of a synergistic rhodium(II)
carboxylate and BINOL phosphoric acid catalyzed efficient
multicomponent reaction of enaldiazo compounds, arylamines,
and aryl aldehydes leading to the first transition-metal-catalyzed
direct synthesis of valuable α-pyrrolylbenzylamines is disclosed.
The reaction is proposed to involve a transient ammonium
ylide of a new class of electrophilic rhodium enalcarbenoid, its regioselective Mannich reaction, and a cyclocondensation cascade.
The methodology was used in a highly diastereoselective synthesis of a binaphthyl based chiral pyrrole.
Scheme 1. N−H Insertion and Multicomponent Reactions via
Protic Ammonium Ylides
yrroles are an important class of heterocyclic compounds
manifested in various natural products, fine chemicals,
P
pharmaceuticals, materials, and catalysts.1−3 Hence, development
of new methodologies toward functionalized pyrroles continues
to be an active research area.4−6 Classical methodologies include
Paal−Knorr, Knorr, and Hantzsch syntheses. The majority of
recent methodologies are focused on transition-metal-catalyzed
isomerizations and annulations.6 Remarkably, these method-
ologies offer efficient construction of polysubstituted pyrroles
with diverse substitution patterns, regioselectivity, and atom
economy. However, despite these advances, the direct con-
struction of chiral pyrroles by transition-metal-catalyzed method-
ologies have remained unexplored. The conventional approaches
for chiral pyrroles involve enantioselective functionalization of the
pyrrole moiety, which offers limited scope.7 Thus, the develop-
ment of new methodologies, in particular those involving
transition-metal-catalyzed direct construction of functionalized
chiral pyrroles would be synthetically highly valuable.
Transition metal catalyzed insertion of X−H (X = N, O, S, B,
Si) bonds into stabilized diazo compounds has evolved as
a powerful strategy for rapid access to valuable heteroatom
containing molecules.8−11 In particular, N−H insertion has been
very useful in delivering biologically important α-amino acids,
α-aminophosphonates and heterocyclic compounds.10 It has
been proposed that N−H insertion into diazo compound 1
proceeds through an initial high energy protic ammonium ylide 2
formation followed by 1,2-proton transfer leading to amine
derivative 3 (Scheme 1a).10 Recently, the Hu and Che groups
have successfully developed elegant multicomponent reac-
tions by trapping protic ammonium ylides 2 (M = Rh2L4) with
various electrophiles, including imines (Scheme 1b), aldehydes,
and enones leading to synthetically valuable 1,2-diamines 4,
1,2-aminols, and pyrrolidine derivatives, respectively.11 We
envisioned that the protic ammonium ylides 5 (Scheme 1c)
derived from our recently designed rhodium enalcarbenoids 612
would offer (a) stabilization due to the extended conjugation and
(b) concomitant vinylogous nucleophilicity toward electrophiles
such as iminium species 7, leading to Mannich product 8 with
new stereogenic centers. These key features of enalcarbenoids 6
Received: May 26, 2014
Published: July 2, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol501508f | Org. Lett. 2014, 16, 3700−3703

Organic Letters
Letter
a13
,
have the potential to offer distinct new classes of cascade reac-
tions for rapid synthesis of nitrogen containing chiral molecules.
Herein, we disclose the design of an efficient multicomponent
reaction, cooperatively catalyzed by rhodium(II) carbxylate and
BINOL phosphoric acid, involving enaldiazo compound 9,12 aryl
aldehyde 10, and amine 11 (R= Ar, Boc) leading to the direct
synthesis of α-(3-pyrrolyl)benzylamines 12 consisting of a new
stereogenic center (Scheme 1c).
Table 1. Optimization Studies
Our studies began with the reaction of diazoenal 9a with
aniline in the presence of a catalytic amount of Rh2(OAc)4 (eq 1).
b
entry
Rh2L4 (mol %)
solvent
temp (°C) time (h) yield (%)
1
2
3
4
5
Rh2(OAc)4(2)
Rh2(OAc)4(1)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(Oct)4(5)
Rh2(esp)4(5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
25
25
25
0
2
2
53
45
62
42
48
79
45
74
75
61
72
69
56
71
68
64
51
56
56
52
2
10
2
45
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
c
6
2
2
d
7
When a solution of diazoenal 9a (0.15 mmol, 1 equiv) in
dichloromethane (DCM, 2 mL) was added slowly over 2 h to a
solution of aniline (0.15 mmol) and 2 mol % of Rh2(OAc)4 in
DCM (1 mL) at 10 °C, pyrrole 13 was obtained in 10% yield,
presumably via ammonium ylide/cyclocondensation cascade.
The yield was improved to 63% when the same reaction was
carried at 25 °C.
8
2
9
C2H4Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
10
11
12
13
14
15
16
2
2
2
Rh2(TFA)4(5)
Rh2(R-DOSP)4(5)
Rh2(S-DOSP)4(5)
Rh2(R-PTAD)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
Rh2(OAc)4(5)
2
2
Encouraged by this result, we next turned our attention to
testing the hypothesis of capturing the transient ammonium ylide
5 (EWG = benzoyl) with an imine electrophile 15. Gratifyingly,
when a solution of 9a (0.14 mmol, in 2 mL of DCM) was added
slowly over 2 h to a mixture of aniline (0.14 mmol), imine 15
(0.14 mmol), 2 mol % of Rh2(OAc)4, and 10 mol % of
( )-BINOL phosphoric acid 14a in DCM (2 mL) at 25 °C,
the α-(3-pyrrolyl)benzylamine 16 possessing a new stereogenic
center was formed in 58% yield (eq 1).13 It is noteworthy that the
Mannich reaction proceeded with complete regioselectivity,
which further promoted the subsequent cyclocondensation step
resulting in [4 + 1]-pyrrolannulation of the multicomponent
reaction (Scheme 1c). In the absence of 14a, only a trace amount
of 16 was formed along with pyrrole 13. In a separate experiment,
when pyrrole 13 was treated with imine 15 (1 equiv), 10 mol % of
Bronsted acid ( )-14a, and 2 mol % of Rh2(OAc)4 in DCM, the
desired product 16 was not formed even after prolonged reaction
time (6 h) at 25 °C. This experiment revealed that the imine
electrophile 15 was captured before the cyclocondensation step
to form pyrrole ring in 16.13 Other Brønsted acids like benzoic
acid, camphorsulfonic acid, p-toluenesulfonic acid, and trifluoro-
acetic acid did not give desired product 16.
To further simplify the reaction, we were curious to know if the
imine 15 can be generated in situ. Delightfully, when diazoenal
9a (1 equiv, 0.14 mmol in 2 mL of DCM) was added slowly to a
mixture of aniline and benzaldehyde (0.28 mmol:0.14 mmol in
2 mL of DCM, prestirred for 1 h in the presence of 4 Å MS),
10 mol % of 14a, and 2 mol % of Rh2(OAc)4, the desired pyrrole
16 was obtained in 53% yield. As shown in Table 1, further
optimization studies revealed that low Rh(II) catalyst loading
leads to diminished yields (45%, entry 2). However, increasing
the catalyst loading to 5 mol % improved the yield (62%, entry 3).
At this stage, we decided to test the role of temperature on the
efficiency of the catalytic process. At lower temperature, the
reaction was sluggish and incomplete even after longer reaction
time (entry 4). High temperature gave diminished yield (48%,
entry 5) due to fast decomposition of the diazo substrate.
Consistent and better yields wereobtained at 10°C (79%, entry 6).
2
2
e
17
2
f
18
2
g
19
2
h
20
2
a
Conditions: aniline/benzaldehyde/9a = 0.28:0.14:0.17 mmol. (R)-
b
c
14a was used for entries 1−16. Isolated yields. Same yield obtained
d
e
with ( )-14a. 5 mol % of (R)-14a was used. (R)-14b was used.
f
g
h
(S)-14c was used. (R)-14d was used. (R)-14e was used.
Use of 5 mol % of ( )-14a gave reduced yield (45%, entry 7).
Among the solvents, halogenated solvents gave clean reactions
and good yields (entries 8 and 9) compared to nonpolar solvent
(entry 10). With respect to catalyst screening, various other Rh(II)
carboxylates promoted the reaction (entry 11−16). However,
Rh2(OAc)4 proved to be a catalyst of choice in terms of efficiency
and cost. Interestingly, the reaction gave only <10% ee for pyrrole
16 despite the use of various chiral phosphoric acids14 (entry 14−
16) and chiral rhodium(II) carboxylate catalysts (entry 17−20).
With the optimized conditions in hand, the generality of the
reaction was tested with various diazoenals 9, anilines 17, and
aryl aldehydes 18 (Scheme 2). Both keto-diazoenals and ester-
diazoenals gave excellent yields of pyrroles 19−23 (71−81%)
with aniline and benzaldehyde. The halo-substituted anilines and
aryl aldehydes also gave very good yields of pyrroles 24−26 (70−
82%). However, the electron-rich aryl aldehydes and anilines
gave diminished yields of pyrroles 28−30 (61−67%), presum-
ably due to the slow rate of Mannich reaction. On the other hand,
electron-deficient anilines and aryl aldehydes gave high yields of
pyrroles 31−35 (70−84%). The reaction was sensitive to steric
environment in anilines. The hindered 2-(trifluoromethyl)-
aniline gave a low yield of pyrrole 36 (61%), whereas 2,4,6-
trimethylaniline did not give the desired pyrrole.
The generality of the methodology was further tested with
versatile Boc-carbamates 37 and preformed Boc-imines 38
of aryl aldehydes (Scheme 3). To our delight, both keto- and
ester-diazoenals smoothly participated in the multicomponent
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Organic Letters
Letter
Scheme 2. Multicomponent [4 + 1] Pyrrolannulation with
Anilines13
Scheme 3. Multicomponent [4 + 1]-Pyrrolannulation with
N-Boc-carbamates
a b 13
,
,
a
b
Conditions: 37:38:9 = 0.13:0.13:0.16 mmol. Isolated yields.
In summary, we have designed a highly efficient multi-
component reaction of diazoenals, arylamines, and aryl
aldehydes cooperatively catalyzed by rhodium(II) carboxylate
and BINOL-phosphoric acid for the first direct synthesis of
valuable α-(3-pyrrolyl)benzylamines with a new stereogenic
center. The reaction is proposed to involve formation of a
transient protic ammonium ylide from the rhodium enalcarbe-
noid, a regioselective Mannich reaction and a cyclocondensation
cascade. The methodology was used in the efficient synthesis of
versatile N-Boc-pyrroles and a highly diastereoselctive synthesis
of binaphthyl-based chiral pyrrole. Further studies are ongoing
toward the mechanistic aspects of this novel multicomponent
reaction and its application to the natural product synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
reaction to deliver densely functionalized N-Boc-pyrrolylamines
39−44 in 62−73% yield. The N-Boc-pyrrole 40 was con-
veniently deprotected to N−H pyrrole 45 in high yield (eq 2).
Experimental details, characterization data, and X-ray crystal
structure data of 24. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sk@iiserb.ac.in.
Notes
To probe the role of chiral aryl aldehyde on establishing the
proximal chiral center in the Mannich step, the multicomponent
reaction was carried with keto-diazoenal 46, 4-nitroaniline, and
chiral binaphthyl aldehyde (S)-47 (eq 3). Although the sterically
crowded environment on 47 retarded the reaction, it played
a critical role on the diastereoselectivity of the chiralpyrrole
product 48. The best diastereoselectivity (92:8) was obtained
with sterically crowded BINOL phosphoric acid (R)-14e.13
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from IISER Bhopal and SERB-DST is
gratefully acknowledged. We thank Mr. Rajbeer Singh and Mr.
Brijesh K. Sharma (NMR facility, IISER Bhopal) for recording
high-field NMR data.
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Letter
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DEDICATION
■
This work is dedicated with respect and affection to Professor
Goverdhan Mehta on his 71st birthday.
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(13) See the Supporting Information for experimental details,
mechanistic study, and characterization.
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