Mechanistic Studies on GarrattâBraverman Cyclization: The Diradical

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Mechanistic studies on Garratt-Braverman Cyclization: The Diradical-Cycloaddition Puzzle Joyee Das, Subhendu Sekhar Bag, and Amit Basak J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00490 • Publication Date (Web): 26 Apr 2016 Downloaded from http://pubs.acs.org on April 27, 2016

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The Journal of Organic Chemistry

Mechanistic studies on Garratt-Braverman Cyclization: The Diradical-Cycloaddition Puzzle Joyee Dasa, Subhendu Sekhar Bag*b and Amit Basak*a

a

Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India b

Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India *Corresponding author Email: [email protected], [email protected],

Abstract

In this work, we present the results of extensive multi prong studies involving fate of deuterium labeled substrates, EPR, trapping experiments and LA-LDI mass spectrometry to sort out the controversies relating to the mechanism of Garratt-Braverman cyclization in two systems, namely bis-propargyl sulfones and ethers. The results are in conformity with a diradical mechamism for the sulfone, while for the ether, the anionic [4+2] appears to be the preferred pathway. This shows that the mechanistic pathway towards GB cyclization is dependent upon the nature of hetero atom (O or S in sulfone) bridging the propargyl arms.

Key Words: Garratt-Braverman Cyclization, Bis-propargyl, sulfone, Ether, Bis-allene, Diradical, EPR

1

ACS Paragon Plus Environment


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Introduction Cycloaromatization reactions1 have become an important research area because of their interesting mechanistic possibilities2 which control the reactivity of molecules undergoing such reactions and the extent of their interactions with biomolecules.3 Several cycloaromatization reactions are known starting from the famous Bergman Cyclization reported first in 1971.4,5 Few years after Bergman’s paper, Garratt and Braverman6.7 independently reported the reactivity of bis-propargyl systems (sulfide, sulfone, ether, amine) under base mediated conditions. The final outcome of the reaction, now popularly known as Garratt-Braverman (GB) Cyclization, was dependent upon the nature of substituent in the propargyl arm as well as the reaction condition. For example, in case of an unsubstituted thioether, a dimeric product was obtained in virtually quantitative yield via the bis-allene (path A).8a The reaction was carried out in two stages: an initial treatment with KOtBu at -65 °C to get the bis-allene followed by warming the latter in CHCl3 to 50 °C. For di-t-butyl propargyl thioether, the product was mainly the cyclobutane-fused thiophene.8a Later on, Garratt et al. reported the isolation of similar products in low yields from all the systems (thioether, ether and amine) using KOH/MeOH.8b For alkyl substituted substrates, 3, 4-disubstitued 5-membered heterocycles were formed (path B).9 On the other hand, aryl or vinyl substituted starting materials provides a new aromatic system via the participation of the aryl or vinyl double bond, ultimately leading to the formation of a naphthalene or benzene fused heterocyclic system (path C).10 All these possibilities are shown in Scheme 1 R

C

X

R

X R

C I

R

a

R

t

X

c

Bu

X

X

R

Bu

V (major)

R III R = aryl/alkene

b

t

IV

X

II R = alkyl

R = tBu

R=H X

H X

X R

VI

X = S, O, NEt

VII

X = S, O, SO2, NMe

Scheme 1: Garratt-Braverman Cyclization 2


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The generally accepted mechanism for the process as is depicted in pathways a-c (Scheme 1) involves the formation of a diradical from a bis-alleneic intermediate8 (Scheme 2A). Support for this mechanism came from various experiments like successful trapping of the diradical with 3O2 to form the endo peroxide11 (in case of sulfide), the non-perturbation of the rate upon varying solvent polarity12 as well as the isolation XIII as an intermediate (Scheme 2A).

In recent years, through a combination of

experiment and computations on the selectivity of aryl substituted bis-propargyl sulfones, the diradical mechanism was shown to be the preferred pathway.13 Moreover, the complete GB selectivity of substrates capable of undergoing multiple reactions could be successfully explained on the basis of diradical mechanism.14 bisallene formation X

X R

C

X

R

VIII

H-shifts

diradical formation X

C

IX

X

H

XI X

X = SO2, O, N

X

R

R

R = Aryl or Alkyl

R

R

A possible intermediate

XII

XIII

Scheme 2A: The diradical mechanism -

base

O

C

O

O R

R

R

XV

XIV -

[4 + 2] Cycloaddition

Protonation Isomerization

O R

H

XVII

-

XVI

O R XVIII

Scheme 2B: The anionic IMDAR Mechanism Some ambiguities still remain regarding the diradical mechanism for the GB process, especially for reactions going through path c in view of the fact that the bis-allene, the progenitor of the diradical, is generated only after double isomerization and also has multiple mechanistic options. In some of the earlier experiments with sulfones by Braverman, 7a the bis-allene was directly generated and hence not much of ambiguity existed for those cases. But in classical GB reaction, where bis-propargyl systems 3



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are the starting materials, bis-allene formation is an important issue which should be a sequential event. If the mono to the bis-allene formation is slow,15 by the time it undergoes isomerization, it may give rise to the same products via an alternate route.

For example, one can draw a [4+2] cycloaddition

(Intramolecular Diels-Alder Reaction (IMDAR) mechanism) to arrive at the products from aryl substituted systems. Such a mechanism has been originally proposed by Iwai and Ide10a and later on reinforced by Kudoh et al.16 for rearrangement of bispropargyl ethers in presence of strong bases like NaH or Triton B in DMSO involving a monoallenic anion followed by an intramolecular Diels-Alder reaction and subsequent quenching of the resulting anion by DMSO (Scheme 2B). The final product was obtained via a 1,5-migration of the anion generated at ring fusion carbon and subsequent quenching. The mechanism was supported by labeling experiments with deuterated solvents and computations. Recently, Balci et al.17 have reported the synthesis of Chromenopyridines exploiting the IMDAR mechanism from an in situ generated azadiene and an alkyne system. Although Kudoh et al.16 synthesized several aryl naphthalenes using their protocol, for their mechanistic study involving deuterium incorporation, the group used a system which can only isomerize to a monoallene as the other arm was disubstituted at the propargyl position thus limiting the generality of such a pathway in systems capable of undergoing isomerization to the bis-allene. Results and Discussion With this backdrop, we undertook a detailed study to address these mechanistic issues. Specifically we have the following questions in mind: i) do all these bis-propargyl systems (S, SO2, O, N) follow the same mechanism or mechanisms are different for different systems considering the variations in the reaction conditions employed for different propargyl systems? ii) if that be the case (different mechanisms), will the selectivity pattern from unsymmetrical systems follow different trend? iii) will it be possible to use appropriately deuterated substrates to discriminate between the mono-allene vs bisallene mechanism? and finally iv) will it be possible to capture any EPR signal during the course of the reaction? The present work was aimed to address these issues and we have been able to provide evidences for the reaction pathways for the ether and the sulfone which are presented in this paper. 4


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The selectivity issue was taken up first. Towards that end, we prepared several unsymmetrically substituted bis-propargyl ethers/sulfones and treated them with a suitable base depending upon the nature of substrate (KOtBu in DMSO for ethers and Et3N in CHCl3 for sulfones) to get an insight into the outcome of GB reaction, the reaction was carried out at room temperature. The product ratio was determined from the integrations for characteristic signals of the two isomers in the 1H−NMR spectrum of the crude reaction mixture. The results of the GB reaction which showed opposite selectivity for the ethers vis-a-vis sulfones are compiled in Table 1. Previously18 we have reported the product ratio for the ether systems using different reaction condition (DBU/Toluene/reflux). The trend of selectivity followed similar pattern. The structures of the products were confirmed mainly on the basis of 1

H−NMR,

13

C−NMR, DEPT-135 and correlation spectroscopy in some cases. For the sulfones, the

major product arises from the preferential participation of the more electron-rich aryl ring while for the ether, the less electron -rich aryl ring predominantly participates. Prima facie, this contrast in selectivity for the sulfone vis-à-vis ether, indicated different mechanism for the two reactions. The results fit well with the anionic cycloaddition mechanism for the ether but not for the sulfone. However, we must keep in mind the different electronic nature of sulfone (-R, -I effects) vis-à-vis the ether (+R, -I) which might explain the different selectivity for the both the reactions even if they involve a common diradical pathway (Figure 1). In case of sulfone, the radical benzylic to the electron donor aryl ring will be captodatively stabilized while in case of ether it will just be the opposite with electron withdrawing aryl group stabilizing the benzylic radical.13, 18 X

For X = O, KOtBu/DMSO/rt/1 h; For X= SO2, Et3N/CHCl3/rt/ 30 min

A

X

X

+ A

A 1a-d 2a-d

3a-d 5a-d

4a-d 6a-d

5



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SM

X

A

Yield (%)

Product ratio

1a

O

2-naphthyl

97

3a:4a (2:1)

1b

O

6-Methoxynaphthyl

94

3b:4b (1:2)

1c

O

4-Methoxyphenyl

95

3c:4c (1:8)

1d

O

2,4-Dimethoxy phenyl

94

3d:4d (1:10)

2a

SO2

2-naphthyl

95

5a:6a (3.16:1)

2b

SO2

6-Methoxynaphthyl

90

5b:6b (5.16:1)

2c

SO2

4-Methoxyphenyl

85

5c:6c (2:1)

2d

SO2

2,4-Dimethoxy phenyl

87

5d:6d (5.16:1)

Table 1: Results of base mediated reaction of sulfones and ethers

. .

..D

. .

O S

O

A

O

..

A

D D= Electron donating groups A =Electron accepting groups

. D

.

+ A

-

O S

O A

.

O+

.

.

D

Figure 1: Differential Electronic nature of Sulfone and Ether We next turned our attention to a more assertive experiment based on the outcome by carrying out the reaction in deuterated solvents. Before carrying out these experiments, we wanted to check the exchangeability of the heterocyclic methylenes in the GB products under basic conditions. Thus, the GB products derived from both the sulfone and the ether were subjected to the respective reaction conditions in presence of deuterated solvents. The phthalans derived from the ether was stirred in d6DMSO in presence of KOtBu whereas the counterpart dihydrothiophene 1,1-dioxide was treated with Et3N in presence of CDCl3 (Scheme 3) to find out the level of deuterium incorporation, if any at C-1 6


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and C-3. The temperature was maintained at the room temperature of 30 °C in both the cases which is also the GB reaction temperature. Interestingly but not unexpectedly, varying degrees of deuterium was found at these positions in the phthalans, the extent of deuteration depends upon the amount of base. With excess of KOtBu in d6-DMSO, 100% deuteration was observed at both the methylene positions. Although lesser extent of deuterium incorporation occurs with 1.0 eq of base, any mechanistic study based on deuterium incorporation at the methylene positions may not be reliable. For the dihydrothiophene 1,1-dioxide, although no such exchange at the methylenes was observed, there was a possibility of incorporation of D during propargyl-allene isomerization. Experimental results showed that no deuterium was incorporated at any position of the product from the reaction of sulfone with Et3N and CDCl3 thus ruling out any D exchange during propargyl-allene isomerization. This observation is important as anionic [4+2] cyclization (IMDAR) suggests deuterium incorporation, especially at C-9. This single observation rules out the anionic IMDAR mechanism for the rearrangement of sulfone, a conclusion also supported by the results obtained from deuterated substrates (as discussed below). A general structure showing the numbering is included in Scheme 3 (Structure A) D

8

9

1

5.0 equiv t OMe KO Bu, DMSO-d6, rt, 1 h

O 4

5

3

OMe 4d

A

D O D D OMe

O

OMe 4d''

H SO2

100%

5.0 equiv Et3N, CDCl3, rt, 1 h

H SO2 H H

No D incorpoartion

10b 10b 1.0 equiv Et3N, CHCl3, rt, 30 min

S O2 8b

Scheme 3: Results of exchange reactions For the rearrangement of labeled substrates having deuterium at both the ortho positions of the phenyl ring, the possible outcome of the deuterium retention, loss or migration are shown in Scheme 4. In case of diradical mechanism, the intermediate XXII has all the D intact. This will be followed by a series of migrations involving H (D). If these migrations are concerted, then highest level of deuterium is expected to be observed at the migrating position. If such migrations are non-concerted and follows in a stepwise manner, less percentage of D incorporation is then expected. For the intermediate sulfone (X = SO2), because of non-aromatic character of heterocycle, 1,5- D-shift (from C-11 to C1) along with a 7



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1,3-H shift from C-4 to C-3 are expected to lead to the creation of the new aromatic ring. The stability of the anion  to the sulfone may also aid the 1,5 shift. 1,3-D migration from C-11 to C-9 was ruled out because that still retains the nonaromatic thiophene dioxide ring. If these processes are concerted, D incorporation at C-1 was expected to the extent of 50% in the final product. However, prima facie, the transoid geometry of the diene framework should prohibit a concerted 1,5-sigmatropic shift thus raising doubts on the expected level of deuteration. No deuterium is expected at C-9 for sulfone; however for the ether, because of the aromaticity of furan, 1,3 shift from C-11 to C-9 can take place. Another 1,3 shift fromC-9 to C-1 will lead to the final product. The extent of deuterium at these positions (C-1 and C-9) depends upon the concertedness of migration and possible exchange with the non-deuterated solvent. For anionic IMDAR mechanism, if a concerted 1,3-H shift from C-11 to C-9 occurs, one can expect high level of deuterium at C-9. Kudoh et al.16 has mentioned in their paper about such a possibility of a concerted H migration via an anionic 1,3- sigmatropic shift from C-11 to C-9 although no evidence to support this was proposed. The incorporation of deuterium at C-1 was explained on the basis of migration of ring junction anion to C-1 through the π-network followed by quenching (d6DMSO). These possibilities are shown in Scheme 4 (numbering has been shown in structure XXVII). With all these information in hand, the pentadeuterated phenyl based bis-propargyl ethers (1dʹ, 7bʹ and 11d´) and sulfones (2cʹ and 8bʹ) were prepared and subjected to the GB conditions in nondeuterated solvents as mentioned earlier. The results for both ethers and sulfones are shown in Table 2. In these cases, although there exist a possibility of exchange of deuterium at C-1 and C-3 positions, presence of any extent of deuterium at these positions can only arise through migration and not through exchange considering the fact that the reaction is carried out in non-deuteriated solvent which is used in large excess.

8


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X

X D

X

C

C

D

D Diradical

Ar

D

D

D

XIX

D

IMDAR

D

C

D

D

XX

D

X

D

Quenching by solvent

DD

Ar

Extent will depend upon if concerted or stepwise and competion from solvent quenching

D

D

1,5-anion migration C-11 to C-1

X

upto 50% if concerted;

Mechanistic Studies on GarrattâBraverman Cyclization: The Diradical

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