A metal-free one-pot cascade synthesis of highly functionalized biaryl-2-carbaldehydes

Article abstract of DOI:10.1039/c4ob01829j

A metal-free one-pot cascade annulation of acyclic substrates dienaminodioate, cinnamaldehydes and allyl amine was achieved for the synthesis of polyfunctional biaryl-2-carbaldehydes. The reaction proceeds at room temperature by a trifluoroacetic acid mediated Diels-Alder pathway. Synthetic applications of the resulting biaryl-2-carbaldehyde have been demonstrated by conversion into an array of diverse molecules with biological and materials chemistry relevance. The present work offers a complementary route to the existing metal mediated cross-coupling methods for the preparation of biaryls.

Full text of DOI:10.1039/c4ob01829j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
A metal-free one-pot cascade synthesis of highly
functionalized biaryl-2-carbaldehydes†
Cite this: Org. Biomol. Chem., 2014,
12, 8588
Chandrasekhar Challa,a,b Jamsheena Vellekkatt,a,b Jaice Ravindranb and
Received 27th August 2014,
Accepted 11th September 2014
Ravi S. Lankalapalli*a,b
DOI: 10.1039/c4ob01829j
www.rsc.org/obc
A metal-free one-pot cascade annulation of acyclic substrates
dienaminodioate, cinnamaldehydes and allyl amine was achieved
for the synthesis of polyfunctional biaryl-2-carbaldehydes. The
reaction proceeds at room temperature by
a trifluoroacetic
acid mediated Diels–Alder pathway. Synthetic applications of
the resulting biaryl-2-carbaldehyde have been demonstrated by
conversion into an array of diverse molecules with biological
and materials chemistry relevance. The present work offers
a complementary route to the existing metal mediated cross-
coupling methods for the preparation of biaryls.
Biaryl synthesis in the presence of copper was described more
than a century ago by Ullman.1 Majority of synthetic strategies
for biaryls rely on transition metal catalyzed cross-couplings
with attention particularly focused on palladium-catalyzed
methods such as Kharasch, Suzuki–Miyaura, Hiyama,
Kumada, Negishi, and Stille coupling reactions.2 Among the
other cross-coupling methods for biaryls include direct aryla-
tion,3 decarboxylative coupling,4 using hypervalent iodine
reagents,5 and other transition metal free conditions.6 Alterna-
tively, annulation of acyclic substrates offers the provision to
synthesize biaryls with diverse functionalities for molecular
complexity.7 Biaryl motifs have been found as key structural
components in a myriad of exotic carbon frameworks which
includes a variety of natural products,8 pharmaceuticals,9
materials,10 chiral ligands11 and agrochemicals12 (Fig. 1).
Given the importance of biaryls in a multitude of appli-
cations there has been a continued interest to complement the
existing methods for biaryl synthesis. We report herein a tri-
fluoroacetic acid (TFA) mediated one-pot synthesis of polyfunc-
tional biaryls using dienaminodioate, cinnamaldehyde, and
Fig. 1 Representatives of biaryl structural motifs.
allyl amine. An array of biaryls with diverse functionalities on
both the phenyl units were synthesized (Table 2). The other
notable facet of the present method is the generation of biaryl-
2-carbaldehyde which serves as a key starting material for the
synthesis of diverse molecules which are of significance in
biology and materials chemistry.13 The dominant method of
choice for biaryl-2-carbaldehyde synthesis has been the
Suzuki–Miyaura reaction,14 and other reports under metal-free
conditions generally lack the substrate scope and are limited
to simple phenyls.7k,15 To the best of our knowledge, this is
the first report towards the synthesis of highly functionalized
biaryl-2-carbaldehydes under metal-free conditions. Thus, the
present study offers a one-pot metal-free alternative for biaryl-
2-carbaldehyde synthesis which was further transformed into
dibenzopyranone, fluorene, 1,4-dihydropyridine (1,4-DHP),
1,2-DHP and bis(indolyl) methane (BIM) (Scheme 3).
We have recently reported 1,2-DHP synthesis by a one-pot
cascade annulation of dienaminodioate 1 and imines gener-
ated from aromatic aldehydes and amines.16 During this
attempt we have also reported utilization of p-nitrocinnam-
aldehyde 2 as the aldehyde component with p-toluidine 3 which
was presumed to produce the 1,2-DHP product containing a
styryl side-chain. Surprisingly, the 1,2-DHP product in CDCl3
aAcademy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
E-mail: ravishankar@niist.res.in
bAgroprocessing and Natural Products Division, CSIR-National Institute for
Interdisciplinary Science and Technology, Thiruvananthapuram-695019, Kerala,
India
†Electronic supplementary information (ESI) available. CCDC 989389. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob01829j
8588 | Org. Biomol. Chem., 2014, 12, 8588–8592
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Scheme 1 (a) Unexpected formation of biaryl under three-component annulation conditions. (b) Biaryl formation via isolation of trienamine
intermediate.
underwent slow rearrangement to a new non-polar product
which was characterized by NMR as a biaryl B (Scheme 1a).
This result led us to doubt the integrity of the 1,2-DHP pro-
duced from cinnamaldehyde. A detailed characterization by
2D-NMR studies (see ESI†) revealed the identity of the pre-
sumed 1,2-DHP from cinnamaldehyde as a trienamine A. To
further confirm the formation of trienamine with a simplified
NMR spectrum (see ESI†), an annulation reaction was per-
formed with dienaminodioate 1′, p-nitrocinnamaldehyde 2 and
propargylamine 3′ which afforded trienamine A′ (Scheme 1b).
The isolated trienamine A′ was further treated with trifluoro-
acetic acid under open air which provided the expected biaryl
B′. Therefore, the reported four 1,2-DHPs derived from cinnam-
aldehydes and crotonaldehyde, from our previous work, stands
corrected to trienamines.
This serendipitous result motivated us to pursue a synthetic
method for biaryls under metal-free and mild conditions.
Accordingly, a direct biaryl formation was envisaged using
TFA–CH3CN with dienaminodioate 1, cinnamaldehyde 2′, and
allylamine 3″ in one-pot. Trienamine formation was immedi-
ate and predominant but the desired biaryl 4 was formed in a
trace amount despite the increase in concentration of TFA
(entry 1, Table 1). The structure of biaryl 4 was further sup-
ported by a single crystal XRD analysis (Fig. 2).17 Interestingly,
a change of solvent to DCM afforded biaryl 4 in 25% yield
(entry 2). However, when MeCN was used along with DCM as a
co-solvent and by increasing the concentration of TFA/2′/3″ to
three equivalents with respect to one equivalent of dienamino-
dioate 1 the reaction afforded biaryl 4 with a 60% yield (entry
3). Further attempts using solvent systems MeCN–CHCl3 (1 : 1)
and MeCN–DCE (1 : 1) resulted in biaryl 4 in 60% and 43%
yields, respectively (entries 4 and 5). There was no biaryl for-
mation when the reaction was attempted either in the absence
of TFA or allylamine (entries 6 and 7). Attempts with other
acids such as FeCl3, trichloroacetic acid, and acetic acid had
no significant improvement in the yield of biaryl 4 (entries
8–10); and there was no biaryl formation in the presence of
Table 1 Optimization of reaction conditions
Ratio
Time
(h)
Yieldc
(%)
Entry Acid (eq.)
2′ : 3″a
Solventb
R1
1
TFA (5)
TFA (1)
TFA (3)
TFA (3)
TFA (3)
—
TFA (3)
FeCl3 (3)
TCA (3)
AcOH
BF3·OEt2 (3) 3 : 3
p-TsOH (3)
TFA (3)
TFA (3)
TFA (3)
1.2 : 1.2 MeCN
1.2 : 1.2 DCM
2
on
4.30
H
H
H
H
H
H
H
H
H
H
H
H
Trace
25
60
60
43
n.d.
n.d.
44
21
47
2
3d
4e
3 : 3
3 : 3
3 : 3
3 : 3
3 : 0
3 : 3
3 : 3
MeCN–DCM
MeCN–CHCl3 on
MeCN–DCE
MeCN–DCM
MeCN–DCM
MeCN
5e
on
60
1
7.25
>96
on
on
on
24
6d
7d
8
9d
10f
11
12
13d
14d
15
16
MeCN–DCM
1.2 : 1.2 MeCN
MeCN
MeCN
MeCN–DCM
MeCN–DCM
MeCN–CHCl3 on
MeCN–CHCl3 on
n.d.
n.d.
3 : 3
3 : 3
3 : 3
3 : 3
3 : 3
OMe 40
NO2 45
OMe 55
NO2 50
on
TFA (3)
a Equivalents of 2′ and 3″, respectively. b Undistilled solvents. c Isolated
yields. d MeCN–DCM (1 : 2). e MeCN–CHCl3 (DCE) (1 : 1). f AcOH–MeCN
(0.25 : 2.5 mL). on = overnight, n.d. = not detected.
BF3·Et2O or p-TsOH (entries 11 and 12). Cinnamaldehydes
with para-substituted methoxy and nitro groups led to the for-
mation of desired biaryls 5 and 6 in 40% and 45% yields,
respectively in the MeCN–DCM (1 : 2) solvent system (entries
13 and 14), while with MeCN–CHCl3 (1 : 1) the yields were 55%
and 50%, respectively (entries 15 and 16). The results from the
latter entries indicate that the electronic influence of para-
substitution in cinnamaldehydes had no direct consequence
on the outcome of the biaryl formation. Further optimization
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8588–8592 | 8589

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 Generality of the reaction
Fig. 2 ORTEP diagram of biaryl 4.
studies by variation of the substrate molar ratio and solvents
could not improve the yield of biaryl significantly (see the
ESI†), which led us to consider a substrate molar ratio of
1 : 3 : 3 : 3 for 1/2′/3″/TFA in MeCN–CHCl3 (1 : 1) (0.1 M of com-
pound 1, 3 mL) as the optimized condition to test the general-
ity of the reaction.
Cinnamaldehydes with diverse mono-, di-, and tri-substi-
tutions that confer varied electronic properties to the phenyl
ring were tested for the substrate scope of the reaction
(Table 2). Simple cinnamaldehydes with para- and ortho-substi-
tutions reacted smoothly to afford biaryls 7a–g in good to
excellent yields. Surprisingly, biaryl product 7e was produced
without any competing involvement of the para-formyl
group. Biaryls 7h–k were produced in reasonably good yields
from disubstituted cinnamaldehydes. Biaryls 7j–k demonstrate
the present method as a viable alternative to the existing
traditional Pd catalyzed cross-coupling methodologies to sur-
mount the chemoselectivity obstacle in multi halogen substi-
tuted substrates. Furthermore, 7f–g and 7i–k mark entry into
the tri and tetra ortho-substituted class of biaryls. Polyfunc-
tional biaryl 7l with tri-substitution in each phenyl unit,
obtained in 38% yield, demonstrates the operational simplicity
and functional group tolerance of the present method.
The generality of this method was further extended towards
substituted heteroaromatic unsaturated aldehydes which
afforded hetero biaryls 7m–n in moderate yields. Cinnam-
aldehydes derived from substituted salicylaldehydes resulted
in biaryls which spontaneously underwent cyclization to produce
benzopyrones 7o–p in good yields, offering a milder alternative
to such products produced by utilizing expensive metal cata-
lysts and pre-functionalized starting materials.18 A one-pot,
four-component reaction towards the existing method was
envisaged to add more dimensions to the methodology. As a
result, with substituted salicylaldehydes in MeOH–MeCN (1 : 1)
the reaction afforded the tricyclic product 7q in 60% yield by
successful incorporation of methanol in the product. Similarly,
the reaction with n-butanol afforded the expected tricyclic
product 7r in 66% yield. Previous methods for biaryls hitherto
achieved multiple substitutions in one of the phenyl rings lim-
iting the other as a simple phenyl unit or with utmost mono-
substitution. Notably, the present methodology offers biaryls
with diverse mono-, di-, and tri-substitution patterns on both
the phenyl units in a one-pot reaction.
Solvent conditions: a DCM–MeCN (2 : 1). b MeOH–MeCN (1 : 1).
c n-BuOH–MeCN (1 : 1).
8590 | Org. Biomol. Chem., 2014, 12, 8588–8592
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Scheme 2 Mechanistic pathway.
The mechanistic pathway for the formation of biaryl is
shown in Scheme 2. The reaction proceeds via the Diels–Alder
reaction through MacMillan’s iminium activation19 of alde-
hyde. The resulting adduct C undergoes rearrangement to a
more stable trienamine intermediate by a loss of proton.
Aromatization to intermediate D can be facilitated by air oxi-
dation and subsequent work-up affords biaryl. The oxidation
step was further confirmed by treating the isolated trienamine
intermediate with DDQ/DCM which produced a facile con-
version to biaryl.
Scheme 3 Transformations of biaryls to various other structural motifs.
Reaction conditions: (a) 7o (1 eq.), Dess–Martin periodinane (3 eq.),
DCM, rt; (b) 4 (1 eq.), ethyl 3-(allylamino)acrylate (2 eq.), p-toluidine
(1 eq.), TFA (1 eq.), MeCN, rt; (c) 1 (1 eq.), 4 (1.2 eq.), p-toluidine (1.2 eq.),
TFA (1 eq.), MeCN, rt; (d) (i) 4 (1 eq.), PhMgBr (5 eq.), THF, 0 °C (ii)
p-TsOH (cat.), toluene, reflux; (e) 4 (1 eq.), indole (2 eq.), p-TsOH (cat.),
ethanol, reflux.
To justify the importance of 2-carbaldehyde in biaryls, a
series of transformations were carried out on biaryls 7o and 4
to afford dibenzopyranone 8, 1,4-DHP 9, 1,2-DHP 10, fluorene
11, and bis(indolyl)methane (BIM) 12 (Scheme 3). A number of
natural products contain benzopyranone as a core feature and
a recent report for its synthesis from biaryl-2-ol involves palla-
dium-catalyzed CO insertion via C–H activation.20 Dibenzo-
pyranone 8 was synthesized from biaryl 7o in a quantitative
yield by the Dess–Martin periodinane oxidation. 1,4-DHP 9
and 1,2-DHP 10 which were synthesized in one step from
biaryl 4, unequivocally, demonstrates a new entry into the
repertoire of aryl scaffolds. Fluorenes which gained promi-
nence in the form of conjugated polymers in display appli-
cations with exceptional electro optical properties are
synthesized by metal-catalyzed annulations.21 Fluorene 11 was
synthesized in two steps in a quantitative yield from biaryl 4 by
the Grignard addition followed by the Friedel–Crafts alkyl-
ation. BIMs are known to exhibit a broad range of important
biological activities against various diseases especially in
cancer inhibition.22 BIM 12 was synthesized in one step from
biaryl 4 and indole in the presence of a catalytic amount
of p-TsOH. The present work for the synthesis of biaryls
under mild conditions, in consequence, presents an efficient
alternative to synthesize such a diverse array of molecules
from biaryl-2-carbaldehydes.
Conclusions
In summary, we have shown a one-pot method for currently
inaccessible polyfunctional biaryls bearing an ortho carb-
aldehyde group under metal-free conditions. We have also
demonstrated the utility of biaryl-2-carbaldehyde by transform-
ation into molecules which are of significance in biology and
materials chemistry.
Acknowledgements
Financial support from The Kerala State Council for Science,
Technology & Environment (KSCSTE), India, grant no. 1422/
2014/KSCSTE is gratefully acknowledged.
Notes and references
1 F. Ullmann and J. Bielecki, Chem. Ber., 1901, 34, 2174–
2185.
2 For reviews, see: (a) S. P. Stanforth, Tetrahedron, 1998, 54,
263–303; (b) C. C. C. J. Seechurn, M. O. Kitching,
T. J. Colacot and V. Snieckus, Angew. Chem., Int. Ed., 2012,
51, 5062–5085.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8588–8592 | 8591

View Article Online
Communication
Organic & Biomolecular Chemistry
3 For reviews, see: (a) G. P. McGlacken and L. M. Bateman,
Chem. Soc. Rev., 2009, 38, 2447–2464; (b) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–
238.
4 L. J. Gooßen, G. Deng and L. M. Levy, Science, 2006, 313,
662–664.
8 G. Bringmann, D. Menche, M. Bezabih, B. M. Abegaz and
R. Kaminsky, Planta Med., 1999, 65, 757–758.
9 K. L. Goa and A. J. Wagstaff, Drugs, 1996, 51, 820–845.
10 (a) C. Nagamani, J. Guo and S. Thayumanavan, J. Polym.
Sci., Part A: Polym. Chem., 2012, 50, 1187–1196;
(b) G. W. Gray, Liq. Cryst., 1998, 24, 5–14.
5 (a) S. K. R. Parumala and R. K. Peddinti, Org. Lett., 2013, 11 R. Noyori and H. Takaya, Acc. Chem. Res., 1990, 23, 345–
15, 3546–3549; (b) G. Jacquemot, M.-A. Ménard, 350.
C. L’Homme and S. Canesi, Chem. Sci., 2013, 4, 1287–1292, 12 M. E. Matheron and M. Porchas, Plant Dis., 2004, 88, 665–
and references therein. 668.
6 (a) N. E. Leadbeater and M. Marco, J. Org. Chem., 2003, 68, 13 For recent reports, see: (a) K. Bera, S. Sarkar, S. Jalal and
5660–5667; (b) C. L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou,
X.-Y. Lu, K. Huang, S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nat.
Chem., 2010, 2, 1044–1049; (c) H. Gao, D. H. Ess,
M. Yousufuddin and L. Kürti, J. Am. Chem. Soc., 2013, 135,
7086–7089; (d) V. Diemer, M. Begaud, F. R. Leroux and
F. Colobert, Eur. J. Org. Chem., 2011, 341–354;
(e) V. Dichiarante, M. Fagnoni and A. Albini, Angew. Chem.,
Int. Ed., 2007, 119, 6615–6618, and references therein.
U. Jana, J. Org. Chem., 2012, 77, 8780–8786; (b) F. Portela-
Cubillo, E. M. Scanlan, J. S. Scott and J. C. Walton, Chem.
Commun., 2008, 35, 4189–4191; (c) Y. Xia, P. Qu, Z. Liu,
R. Ge, Q. Xiao, Y. Zhang and J. Wang, Angew. Chem., Int.
Ed., 2013, 52, 2543–2546; (d) S. Wertz, D. Leifert and
A. Studer, Org. Lett., 2013, 15, 928–931; (e) X. Yu and X. Lu,
Adv. Synth. Catal., 2011, 353, 569–574.
14 M. Sindelar, T. A. Lutz, M. Petrera and K. T. Wanner,
J. Med. Chem., 2013, 56, 1323–1340.
7 For selected references see: (a) A. Diallo, Y.-L. Zhao,
H. Wang, S.-S. Li, C.-Q. Ren and Q. Liu, Org. Lett., 2012, 14, 15 B.-C. Hong, H.-C. Tseng and S.-H. Chen, Tetrahedron, 2007,
5776–5779; (b) J. Zheng, Y. Huang and Z. Li, Org. Lett., 63, 2840–2850.
2013, 15, 5064–5067; (c) D. Xue, J. Li, Z.-T. Zhang and 16 C. Challa, M. John and R. S. Lankalapalli, Tetrahedron Lett.,
J.-G. Deng, J. Org. Chem., 2007, 72, 5443–5445; 2013, 54, 3810–3812.
(d) A. Sharma, J. Pandey and R. P. Tripathi, Tetrahedron 17 CCDC 989389 contains the supplementary crystallographic
Lett., 2009, 50, 1812–1816; (e) B. O. Ashburn and data of compound 4.
R. G. Carter, Angew. Chem., Int. Ed., 2006, 45, 6737–6741; 18 A. Das, H.-K. Chang, C.-H. Yang and R.-S. Liu, Org. Lett.,
(f) L. Minuti, A. Temperini and E. Ballerini, J. Org. Chem., 2008, 10, 4061–4064.
2012, 77, 7923–7931; (g) V. Specowius, N. Kelzhanova, 19 G. Lelais and D. W. C. MacMillan, Aldrichimica Acta, 2006,
Z. A. Abilov and P. Langer, Monatsh. Chem., 2012, 143, 39, 79–87.
1151–1156; (h) L. Li, M.-N. Zhao, Z.-H. Ren, J.-L. Li and 20 T.-H. Lee, J. Jayakumar, C.-H. Cheng and S.-H. Chuang,
Z.-H. Guan, Org. Lett., 2012, 14, 3506–3509;
(i) H. Kinoshita, H. Takahashi and K. Miura, Org. Lett.,
Chem. Commun., 2013, 49, 11797–11799, and references
therein.
2013, 15, 2962–2965; ( j) M. Shanmugasundaram, M.-S. Wu 21 (a) T.-P. Liu, C.-H. Xing and Q.-S. Hu, Angew. Chem., Int.
and C.-H. Cheng, Org. Lett., 2001, 3, 4233–4236;
(k) D. Tejedor, C. Mendez-Abt, L. Cotos, M. A. Ramirez and
Ed., 2010, 49, 2909–2912; (b) D. J. Gorin, I. D. G. Watson
and F. D. Toste, J. Am. Chem. Soc., 2008, 130, 3736–3737.
F. Garcia-Tellado, Chem.
3321.
–
Eur. J., 2011, 17, 3318– 22 M. Shiri, M. A. Zolfigol, H. G. Kruger and
Z. Tanbakouchian, Chem. Rev., 2010, 110, 2250–2293.
8592 | Org. Biomol. Chem., 2014, 12, 8588–8592
This journal is © The Royal Society of Chemistry 2014