Intramolecular Baylis-Hillman reaction: synthesis of heterocyclic molecules

The Baylis-Hillman (BH) [also known as the Morita-Baylis-Hillman (MBH)] reaction is a versatile atom-economic C-C bond forming reaction between the α -position of activated alkenes and electrophiles under the influence of a catalyst and provides interesting classes of densely functionalized molecules. Its intramolecular version is yet another fascinating reaction by itself, producing various carbocylic and heterocyclic compounds of synthetic and medicinal relevance. Applications of the intramolecular Baylis-Hillman reaction in obtaining heterocyclic molecules of different ring sizes and also to the synthesis of various natural products/bioactive compounds containing heterocyclic frameworks are presented in this brief review.


Introduction
2][3][4] Now it is possible to synthesize any organic compound that is needed.6][7][8][9] The Baylis-Hillman (BH) reaction 10,11 [also known as the Morita 12,13 -Baylis-Hillman (MBH) reaction] is one such important C-C bond forming reaction, providing densely functionalized molecules in an atom-economical process (Figure 1).This is a three component reaction and involves C-C bond formation between the α-position of activated alkenes with electrophiles under the influence of a catalyst.One of the interesting and useful aspects of this reaction is that it usually provides molecules having a minimum of three functional groups in proximity, that is, α,αto each other.Over the past three decades this reaction has grown from obscurity (actually buried in the literature) to a high level of popularity and applicability.It is now a very wellknown organic reaction and is widely used as a powerful synthetic tool in organic chemistry. 14  In the most widely accepted mechanism of this fascinating carbon-carbon bond-forming reaction four steps are believed to be involved.A model case is presented in Scheme 1 by taking as an example the reaction between methyl acrylate and benzaldehyde catalyzed by DABCO.The first-step involves addition of the catalyst to the activated alkene (methyl acrylate) in a Michael fashion to generate in situ a zwitterionic enolate (A).The second step proceeds by addition of the zwitterionic enolate (A) to the electrophile (benzaldehyde) to give a zwitterionic aldol adduct (B) which in a third step undergoes a proton shift from the carbon αto the ester group to oxygen ion to generate a zwitterion (C).In the fourth step, the catalyst (DABCO) is released to produce the densely functionalized adduct, which is normally referred to as the Baylis-Hillman adduct (D).The exponential growth of this reaction may be attributed to the five important features: (1) It is an atom-economical C-C bond forming reaction.(2) This is an organo-catalytic reaction because most of the catalysts are organic molecules (tertiary amines and phosphines).(3) It creates a chiral center in the product in the case of prochiral electrophile thus providing opportunities to develop its asymmetric version.(4) If the substrate contains both the activated alkene and electrophilc components in appropriate positions there is a possibility of performing intramolecular BH reaction producing various carbocycles and heterocycles.It, thus, creates opportunities for designing such substrates for intramolecular BH reaction and also offers opportunities to develop its asymmetric version.(5) It produces molecules containing a minimum of three proximal functional groups which are of tremendous potential in synthetic and mechanistic organic chemistry.In fact the wide popularity and applicability of this reaction can be easily understood by publications of a number of major [14][15][16][17][18][19][20][21][22] and mini reviews [23][24][25][26][27][28][29][30] and more than 3200 research articles during the past three decades.
The first intramolecular Baylis-Hillman reaction was reported as early as 1992 by Frater and co-workers. 35In fact, this is a landmark publication in the sense that ketones are used as electrophile components (Equation 1).They have also reported intramolecular BH reaction of the ene-ester (α,β-unsaturated ester)-ketone substrate under the influence of chiral catalysts, (-)-CAMP and Li-quinidinate (Equations 2 and 3). 35Even though the yields and enantioselectivities are not that high, this strategy paved the way for intramolecular BH-reaction, its asymmetric version and also demonstrated the possible application of ketones as electrophiles in the BH-reaction. 35ubsequently various substrates and strategies were designed for intramolecular BH-reaction.This mini review presents the literature on the intramolecular Baylis-Hillman reaction and its asymmetric version with an emphasis on the synthesis of heterocycles and application to the synthesis of natural products / bioactive compounds containing heterocyclic frameworks.

IBH reactions: activated alkene (α,β-unsaturated ester)-aldehyde system
Drewes and co-workers reported an interesting intramolecular Baylis-Hillman reaction of acrylate-aldehyde 1 (obtained via the treatment of salicylaldehyde with acryloyl chloride) in presence of DABCO which provided the coumarin salt 2 as a major product and the rearranged B-H-alcohol 3 as a minor product (Scheme 3). 36It is believed that initially the Baylis-Hillman adduct was formed which was subsequently converted into coumarin-chloride salt on reaction with CH 2 Cl 2 and DABCO (Scheme 3).

IBH reactions: activated alkene (α,β-unsaturated amide)-ketone system
Since the intramolecular BH reactions are faster in the case of acrylamide-aldehyde system 13 for obtaining α-methylene-γ-lactam derivatives 15 (Scheme 8) it occurred to us that this strategy might be extended to acrylamide-ketone system 22.We were pleased to observe that these reactions were successful and provided a simple protocol for obtaining α-methylene-γ-lactam derivatives 23 containing a tertiary alcoholic functionality in good yields (Equation 5). 41This study demonstrates the applicability of ketones as electrophiles in BH reactions if substrates are designed appropriately.Equation 5. IBH reaction: Synthesis of α-methylene-γ-lactams having tertiary alcohol group.

Unusual-intramolecular Baylis-Hillman reaction
An interesting intramolecular organometallic variation of BH reaction of substrates containing ruthenium-arene complexes (26) as an electrophile component and less reactive acrylamide as activated alkene component using tributylphosphine/NaH, providing spirolactam-ruthenium frameworks (27), was reported by Pigge and co-workers; two examples are given in Scheme 11. 43 They have also performed demetallation of these products 27 using CuCl 2 to provide spirocyclohex-2,5-dien-4-one derivatives 28 (Scheme 11). 43Similar treatment of enantiomerically pure acrylamide-ruthenium-arene complex 29 with tributylphosphine/NaH provided the spiro compound 30 which on oxidative demetallation with CuBr 2 /CO gave the corresponding oxidized product 31 in enantiomerically pure form in 55% yield (Scheme 12).When Pigge and co-workers used the β,β-disubstituted acrylamide derivative 32 as a substrate the double bond migrated product 33 was obtained as a major compound (one example is given in Equation 6). 43Similarly in the case of substrate 34, double bond migrated product 35 was obtained exclusively (Scheme 13). 43Pigge and co-workers subsequently extended this methodology for polycyclic systems.Two examples are presented in Scheme14. 44Treatment of acrylamide-ruthenium-arene complexes 36a and 36b with tributylphosphine/NaH gave tricyclic compounds 37a and 37b which on oxidative demetallation with CuBr 2 /CO provided rearomatized compounds 38a and 38b respectively (Scheme 14).In all these substrates the benzylic carbon contains at least one hydrogen atom.However when they employed the substrate containing a quaternary benzylic carbon (39) they did not obtain the expected spiro product 41; instead the 3-benzazepine derivative 40 was obtained via orthocyclization (Scheme 15). 44Cp RuCp Bu 3 P (1.0 eq.) NaH (2.0 eq.)

Asymmetric IBH reactions of substrates containing activated alkene and prochiral electrophile components using chiral catalyst.
Our research group has examined the possibility of achieving enantioselectivity in intramolecular Baylis-Hillman reaction using quinine and quinidine as catalysts in the case of N-formylmethyl-N-phenyl acrylamide (13, Ar = Phenyl, n = 0).Although the resulting N-phenyl-3-methylene-4-hydroxy-γ-lactam (15, Ar = Phenyl, n = 0) was obtained in low (10% and 5%) enantioselectivities (Equation 9), this strategy certainly indicates that there is a possibility of achieving high selectivity by employing an appropriate chiral catalyst. 39talyst (1.0 eq.) t BuOH, reflux 30 h catalyst = quinine: 65 %, ee: 10 % catalyst = quinidine: 63 %, ee: 5% Unfortunately this aspect did not receive adequate attention from chemists.We are sure in the coming years it will receive the attention it deserves from synthetic chemists and grow further.

Application to biologically active molecules and natural products
Intramolecular asymmetric BH reactions providing heterocyclic compounds have been successfully employed in the synthesis of number of bioactive compounds and natural products.This section describes such applications of intramolecular BH reactions.
In 2004 Corey and co-workers 48 reported a meticulous application of the intramolecular BHreaction as the key step in a total synthesis of the biologically important natural product salinosporamide A (64) using L-threonine (59) as the starting material (Scheme 21).In this strategy they employed an intramolecular BH reaction of 60 (substrate containing acrylamide as activated alkene component and ketone as electrophile component) in the presence of a catalytic amount of quinuclidine as the key step to provide the resulting adducts 61 and 62 in 9:1 diastereoselectivity in 90% yield.The major compound 61 was selectively alkylated to provide the desired compound 63 (which was subsequently transformed into salinosporamide A 64 (Scheme 21, Path A). 48One year later Corey and co-workers came up with improved reaction conditions (Path B: titanium isopropoxide/cyclopentylmagnesium chloride/ and iodine) for performing the intramolecular BH reaction of the substrate 60 to produce the resulting adduct 61 in 99:1 diastereoselectivity (Path B, Scheme 21). 49The major compound 61 was subsequently transformed into analogue 65 of salinosporamide A 64 (Scheme 21, Path B). 49  Aggarwal and co-workers have elegantly used intramolecular Baylis-Hillman reaction as the key step in the synthesis of the natural product (+)-heliotridine 71 and its unnatural isomer (-)retronecine 72.Thus the IBH reaction of the in situ generated α,β-unsaturated aldehyde (activated alkene component)-iminium ion (electrophilic component) system 69 using TMSOTf/BF 3 .OEt 2 /SMe 2 gave the BH adduct 70 which was conveniently transformed into (+)heliotridine 71 and its unnatural isomer (-)-retronecine 72 via the reaction with LAH following the reaction sequence illustrated in Scheme 22. 50 The required in situ generated α,β-unsaturated aldehyde (activated alkene component)-iminium ion system 69 was easily obtained from the corresponding precursor 68 (which was readily accessible from pyrrolidin-2-one derivative 66 via the treatment with acrolein using Hoveyda-Grubbs catalyst 67) following the reaction sequence shown in Scheme 22.   Intramolecular BH reactions of molecule 80 having an α,β-unsaturated aldehyde-iminium ion system has been employed by Tamura and co-workers synthesis of the natural products/biologically active molecules grandisines B, D and F (81, 82 and 83) according to the sequence shown in Scheme 24. 52,53The required α,β-unsaturated aldehyde-iminium ion system 80 was prepared from easily accessible pyrrolidin-2-one derivative 79 (Scheme 24).

O
Webber and Krische 54 have elegantly used intramolecular BH-reaction as the key step in formal synthesis of (±)-quinine (Scheme 25 -Path A).Thus IBH reaction of enone (activated alkene component)-allyl carbonate (electrophilic unit) system 84 provided the corresponding product 85 which was conveniently transformed into Jacobsen's diene (the key intermediate for synthesis of quinine). 55They have also used the IBH product 85 in the total synthesis of (±)- Formal synthesis of (±)-quinine and total synthesis of (±)-7-hydroxyquinine

Intramolecular BH reactions (activated alkene-activated alkene system) [also known as intramolecular Rauhut-Currier (IRC) reaction]
In the BH reaction, if the electrophile is also an activated alkene, then such reactions are known as Rauhut-Currier reactions.2][33][34] However, very few reports have appeared for obtaining heterocyclic compounds.This section presents such examples.Oshima and co-workers reported a facile protocol for obtaining tetrahydro-2H-pyran derivative 88 with high stereoselectivity via intramolecular vinylogous Baylis-Hillman (Rauhut-Currier) reaction of substrate 87 (containing enone-enone system) using TiCl 4 / nBu 4 NI as shown in Equation 10.A highly reactive enal was utilized as the activated alkene component for coupling with eneester as electrophile component (as shown in compound 93) in an intramolecular Rauhut-Currier reaction by Roush and co-workers, thus providing an interesting strategy for obtaining the 2,5dihydrofuran derivative 94 (Equation 12).Luis and Krische reported a facile chemoselective intramolecular Rauhut-Currier reaction of vinyl thiolate (as activated alkene component)-vinyl sulfone (as electrophile component) system 95 under the catalytic influence of tributylphosphine for obtaining piperidine derivative 96 as shown (Equation 13).

Asymmetric intramolecular Rauhut-Currier reactions
A convenient procedure for the synthesis of 2-(3-nitro-2H-chromen-2-yl)acetate 101 and 2-(3nitro-2H-thiochromen-2-yl)acetate derivatives 102 in high enantioselectivities via asymmetric intramolecular Rauhut-Currier reaction of 97 and 98 respectively using a chiral catalyst 100 (in the presence of 99) was reported by Xiao and co-workers (Equation 14). 60Sasai and co-workers have used chiral phosphine catalysts 104 for highly diastereo-and enantio-selective intramolecular Rauhut-Currier reaction of 103 for obtaining α-alkylidene-γbutyrolactones 107 (Scheme 26, Path A). 61 Subsequently Zhang and coworkers utilized phosphine catalysts 105 and 106 for similar enantioselective Rauhut-Currier reaction (Scheme 26, Paths B and C) of 103 to provide the resulting adducts 107 in high enantioselectivities. 62 Sasai and coworkers also used trimethylated compound 108 for Rauhut-Currier reaction under similar conditions to provide the resulting α-alkylidene-γ-butyrolactone 109 in 70 % ee (Scheme 27, Path A). 61 When the same reaction was performed in the presence of Brønsted acid (BA) (2-naphthol) the resulting bicyclic compound 109 was obtained in 93 % ee (but in 38 % yield) (Scheme 27, Path B). 63 It is interesting to note that the Zhang's catalyst 105 provided better selectivities for intramolecular Rauhut-Currier reaction of 108 thus producing the resulting adduct 109 in 98 % ee and in high yield (89 %) (Scheme 27, Path C).Very recently Spring and co-workers have utilized peptidic phosphine 111 and sulfonamide phosphine 104 as chiral catalysts for asymmetric intramolecular Rauhut-Currier reaction of acrylate-enones 110 for the synthesis of chromanone derivatives 112 in good enantioselectivities as shown in the Equation 15. 64 It is interesting to note that when R is 4-nitro group in 110 no reaction occurred in the case of both the catalysts.It is quiet fascinating to note that Chi and co-workers 65 have proposed an interesting reaction pathway (a plausible mechanism-Scheme 28) involving intramolecular Rauhut-Currier reaction in their work on chiral phosphine (104) catalyzed enantioselective intramolecular [2+4] annulation of acrylate-α,β-unsaturated imine systems (113), providing tricyclic heterocyclic compounds (114) in high diastereo and enantio selectivities (Equation 16).In fact, in order to prove the mechanism proposed, they isolated the intramolecular Rauhut-Currier adduct 115 using triphenylphosphine as a catalyst.

Applications of intramolecular Rauhut-Currier reactions
Roush and co-workers reported an elegant synthesis of (-)-spinosyn-A 116 and its analogue spinosyn-A pseudoaglycon 117 using intramolecular BH-(intramolecular Rauhut-Currier) reaction as a key step (Scheme 29). 66,67 he IRC reaction of 118 provided the corresponding adduct 119 as the major product along with two minor products 120 and 121.The major product was transformed into (-)-spinosyn-A 116 and its analogue spinosyn-A pseudoaglycon 117 following the reaction strategy as shown in Scheme 29. 66,67

Future Challenges and Projections
Although there are not many publications so far on the applications of intramolecular Baylis-Hillman reaction for obtaining heterocyclic compounds, from this brief review it is quite clear that it is an extremely convenient and useful protocol for the synthesis of heterocyclic compounds containing oxygen, nitrogen or sulfur.Literature survey also clearly shows that in comparison to the utility of intramolecular Baylis-Hillman reaction for obtaining carbocyclic systems, such reactions for the synthesis of heterocyclic compounds have not been systematically explored, and only a few synthetic protocols have been reported for 5/6 membered heterocyclic compounds.If substrates are designed appropriately it is possible to synthesize any heterocyclic compounds (including medium and large rings) of medicinal relevance.Thus this strategy offers many opportunities and challenges to the synthetic heterocyclic chemists.The asymmetric version is yet another challenge.There are a few reports on asymmetric intramolecular BH reactions and several aspects have not been yet explored.This is indeed a present day requirement and challenge.We predict that during the coming ten years this aspect will be followed up and exciting results will be obtained.There is also the possibility to use this strategy (both achiral and chiral versions) for the synthesis of heterocyclic compounds with two or more hetero atoms.This aspect has not so far been considered seriously and it can be expected that it will also receive appropriate attention in the coming years and fascinating results can be predicted.There is unexplored possibility of synthesizing spiro compounds 130 using two intramolecular BH reactions of 129 (Equation 17).This needs to be addressed in the coming years.Thus, the intramolecular BH reaction offers unending opportunities for designing strategies for obtaining heterocyclic compounds.

Conclusions
From this brief review it is quite clear that although intramolecular Baylis-Hillman reaction provides important classes of useful heterocyclic compounds of medicinal relevance, this aspect has not received much attention from organic and medicinal chemists.The main objective of writing this review is to draw attention to this apparent neglect.We predict that this fascinating area of the Baylis-Hillman reaction will receive considerable attention from synthetic chemists in the coming years and useful and interesting themes will be developed so as to demonstrate its power in synthetic, mechanistic and medicinal chemistry.

Figure 1 .
Figure 1.The Baylis-Hillman reaction at a glance.

Scheme 24 .
Scheme 24.IBH reaction as a key step in the synthesis of grandisines B, D and F.

Scheme 28 .
Scheme 28.A plausible mechanism involving intramolecular Rauhut-Currier reaction in the synthesis of tricyclic compounds 114.

Equation 17 .
Two intramolecular BH reactions: synthesis of spiro compounds.
IBH reaction as a key step in synthesis of salinosporamide A and its analogue.