Reductive Alkylation of Thioamides with Grignard Reagents in the

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Reductive Alkylation of Thioamides with Grignard Reagents in the Presence of Ti(OiPr)4: Insight and Extension Fabien Hermant,† Ewelina Urbańska,†,‡ Sarah Seizilles de Mazancourt,† Thomas Maubert,† Emmanuel Nicolas,§ and Yvan Six*,† †

Laboratoire de Synthèse Organique (DCSO), UMR 7652 CNRS/Ecole Polytechnique, 91128 Palaiseau Cedex, France Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland § Laboratoire de Chimie Moléculaire (LCM), UMR 9168 CNRS/Ecole Polytechnique, 91128 Palaiseau Cedex, France ‡

S Supporting Information *

ABSTRACT: The reductive alkylation of thioamides by Grignard reagents in the presence of Ti(OiPr)4 is the subject of a study involving 20 different substrates. The influence of various parameters has been evaluated, showing notably that the yields of this moderately efficient process can be improved in several cases by applying a slow addition of the Grignard reagent. The results presented in this contribution also provide new insight into the reactivity of the proposed key intermediates, namely, a metalated iminium species and, ultimately, an α-metalated amine. Interestingly, by control of the temperature and the amount of Grignard reagent engaged, the reaction can be directed toward the selective formation of the former titanium intermediate complex. This represents an extension of the original method, allowing the synthesis of various previously inaccessible substituted amines by subsequent addition of a nucleophilic reagent. This role can be played not only by organomagnesium compounds but also by alkyllithium reagents, alkyltitanium(IV) complexes, and lithium aluminum hydride. The properties of the α-metalated amine final intermediate have also been explored, demonstrating that this complex is a poor nucleophile but can act as a radical precursor, which is especially evidenced when the resulting radical species are stabilized. Overall, this chemistry thus proves unexpectedly rich and can plausibly lay the basis for the development of new applications in the future.

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INTRODUCTION The development of new synthetic transformations based on the combined use of Ti(OiPr)4 (or sometimes another alkoxytitanium(IV) species) and Grignard reagents has emerged from the pioneering work of the group of Kulinkovich at the end of the 1980s/beginning of the 1990s.1 These new methods now constitute a whole family of fairly general reactions,2 the most prominent of which are the cyclopropanation of esters (the Kulinkovich reaction),1,2 the synthesis of aminocyclopropanes from amides (the de Meijere variation)3 or from nitriles (the Bertus−Szymoniak variation),4 and the functionalization of alkynes via titanacyclopropene species (the Sato method).5 Typically, all of these methods use Grignard reagents having hydrogen atoms at the β position. They are thought to involve the initial formation of a titanacyclopropane complex A (Scheme 1). In particular, both nPrMgX and iPrMgX are assumed to give A1, while cC5H9MgX and cC6H11MgX are precursors of A2 and A3, respectively. In this context, we recently began to study the transformations of thioamides 1 under Kulinkovich-type conditions and found that they typically undergo a reductive alkylation process (Scheme 2).6 To explain this transformation, we put © 2014 American Chemical Society

Scheme 1. Generation of Titanacyclopropane Species from Ti(OiPr)4 and Grignard Reagents with β Hydrogen Atoms

forward a ligand exchange reaction of the intermediate A with the thiocarbonyl group, generating a thiatitanacyclopropane complex B. This species could be in equilibrium with a metalated iminium complex C. Attack of the Grignard reagent, Special Issue: Catalytic and Organometallic Chemistry of EarthAbundant Metals Received: June 6, 2014 Published: July 28, 2014 5643

dx.doi.org/10.1021/om500603v | Organometallics 2014, 33, 5643−5653

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Scheme 2. Reductive Alkylation of Thioamides by Grignard Reagents in the Presence of Ti(OiPr)4: General Equation and Proposed Mechanism

used in excess, would then form the organotitanium species D, protonolysis of which would account for the production of the reductive alkylation products 2. Thioamides fitted with a terminal alkene function separated from the nitrogen atom by a two-carbon chain represent a special category of substrates that preferentially undergo intramolecular aminocyclopropanation rather than reductive alkylation (Scheme 3). This process has been the subject of a Scheme 3. Intramolecular Cyclopropanation of Thioamides Fitted with a Suitable ω-Alkenyl Group at the Nitrogen Atom

Figure 1. Thioamide substrates 1a−t.

Choice of the Solvent. Overall, ether solvents such as tBuOMe, THF, Et2O, and cC5H9OMe can be employed, with some variations in the results (see Table 5 for results in the latter two solvents). One example run in cyclohexane gave a significantly poorer result than in tBuOMe or THF (synthesis of 2eb, Table 1). CH2Cl2 is not a suitable solvent (synthesis of 2oc, Table 3). Substrate Scope. The yields obtained from non-alkenyl acyclic substrates are typically moderate, and thioformamides generally tend to perform somewhat better than thioacetamides (Table 1, 2ab vs 2eb, 2bb vs 2gc). Secondary thioamides were expected to be unsuitable substrates because of the reactivity of the N−H bond. This point was verified by the reductive alkylation of N-benzylthioacetamide (1d), which proceeded in 10% yield only. As mentioned in the Introduction, thioamides fitted with a CHCH2 olefin function separated from the nitrogen atom by a two-carbon chain undergo intramolecular cyclopropanation via the intermediate complex E. With an additional substitution grafted onto the alkene group, the yield of this process typically drops to 5−10%. The reductive alkylation products are then obtained in around 30% yield from the 1,2-disubstituted alkene substrates 1i and 1j but in only 6% yield from the 1,1-disubstituted alkene 1k (Table 2). Satisfactory yields can be restored by increasing the length of the spacer, even in the case of monosubstituted olefins. This is illustrated by the conversion of the N-hex-5-enyl substrate 1m into the tertiary amine 2mb, which proceeds in 48% yield. In the case of thiolactams, good results can be achieved, especially in the thiopyrrolidine series 1n−q, with yields of up to 81% (Table 3). The reaction appears to be significantly less efficient with six-membered-ring thiolactams (2sb vs 2ob). It is interesting to note that starting from the β-lactam 1t, the corresponding azetidine 2tb can be obtained, albeit in only 28% yield. Effect of a Coordinating Group. The presence, at the nitrogen atom, of a substituent fitted with an ether group that is able to coordinate to the titanium center was anticipated to favor the ligand exchange process generating the intermediate B

separate study.7 It is proposed that the intermediate E is formed in this case, possibly via B. Ring opening to afford a zwitterionic complex F followed by the formation of the three-membered ring according to an SE2(back) process would give the aminocyclopropane product. This mechanism is thus analogous to the accepted pathway for the intramolecular Kulinkovich−de Meijere reaction of the corresponding carboxylic amide substrates.3 The present contribution focuses on the reductive alkylation process and reports the results of new studies aimed at supporting or challenging the mechanism displayed in Scheme 2 as well as at extending the possibilities offered by this chemistry.

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RESULTS AND DISCUSSION Thioamide Substrates. The structures of the thioamides used in this work are presented in Figure 1. These substrates include nonchiral and chiral compounds, acyclic thioamides, and thiolactams with various ring sizes. Results under the Initially Established “Standard” Conditions. The results of the transformations of these thioamides 1a−t under the initially established standard conditions, typically involving the use of 1.5 equiv of Ti(OiPr)4 and 4.0 equiv of Grignard reagent, are presented in Tables 1, 2, and 3. Several aspects are worthy of comment. 5644


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Table 1. Reductive Alkylation of Acyclic Thioamides 1a−h by Grignard Reagents in the Presence of Ti(OiPr)4a,b

a

Reactions were typically run using 1.5 equiv of Ti(OiPr)4 and 4.0−4.5 equiv of Grignard reagent added over 5−30 min. bYields were estimated by NMR analysis of the crude products. Yields in parentheses are for the isolated products. cA dimeric byproduct 3cb was formed in 30−36% yield. See the text for details. dA secondary amine 4h formally resulting from hydrolysis of the thioamide was produced in 58% yield.

Table 2. Reductive Alkylation of N-Alkenylthioamides 1i−m by Grignard Reagents in the Presence of Ti(OiPr)4a,b

a

Reactions were typically run using 1.5 equiv of Ti(OiPr)4 and 4.0 equiv of Grignard reagent added over 3−8 min. bYields were estimated by NMR analysis of the crude products. Yields in parentheses are for the isolated products. cA secondary amine 4i formally resulting from loss of the thiocarbonyl group was produced in 48% yield. dThe secondary amine byproduct 4k was produced in 36% yield. eThe secondary amine byproduct 4l was produced in 33% yield in tBuOMe and 20% yield in THF. f40% unreacted starting material was observed in the crude product.

Choice of the Grignard Reagent. First, it is worth noting that starting from thioamide 1a in THF, essentially no reaction takes place when the Grignard reagent engaged is MeMgBr; no trace of the reductive alkylation product 2ae is observed. Since only Grignard reagents with β-hydrogen atoms can lead to the generation of titanacyclopropane species A, this result strongly supports the essential role of this type of intermediate complex in the reductive alkylation process (Scheme 2). The other Grignard reagents employed (cyclopentylmagnesium chloride, cyclohexylmagnesium chloride, isopropylmagnesium chloride, and n-propylmagnesium chloride) all lead to the corresponding tertiary amine products 2. Diastereoselectivity. The presence of a stereogenic center directly attached to the nitrogen atom of the thioamide substrate 1 does not generally induce high levels of

(see Scheme 2). Indeed, this idea was implemented successfully in related reactions involving ligand exchange with olefins.8 In the present transformation, the facilitating effect is not so clear and moderate at best. For instance, with cyclohexylmagnesium chloride in tBuOMe, the ether compounds 1f and 1m are converted into the amines 2fb and 2mb in 36 and 42% isolated yield, respectively, which is to be compared with the reaction of thioamide 1e devoid of any ether function, which proceeds in slightly lower yield (30%) under the same conditions. The same reductive alkylation of the much bulkier thioamide 1h proceeds in only 24% yield in spite of the presence of an ether group. In the thiolactam series, the best yields are achieved with the benzyloxy substrate 1o, but 1n, 1q, and 1r perform better than the ethers 1p and 1s. 5645


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Table 3. Reductive Alkylation of Thiolactams 1n−t by Grignard Reagents in the Presence of Ti(OiPr)4a,b

a

Reactions were typically run using 1.5 equiv of Ti(OiPr)4 and 4.0−4.5 equiv of Grignard reagent added over 2−30 min. bYields were estimated by NMR analysis of the crude products. Yields in parentheses are for the isolated products. cOnly the structure of the major diastereoisomer is displayed. dThis product was not isolated because it underwent a rapid cyclization by an intramolecular SN2 reaction (see Scheme 5). eYield after an additional step consisting in an intramolecular SN2 reaction (see Scheme 5).

diastereoselectivity. In the cases of the chiral pyrrolidine-2thiones 1o and 1p and of the chiral piperidine-2-thione 1s, the introduction of the alkyl group proceeds with a moderate preference for the formation of the cis diastereoisomers (Table 3).9 Overall, the selectivities observed range from 50:50 to 72:28, the latter result being obtained in the synthesis of 2oc in THF. Competitive Processes. The undesired secondary amines 4, formally resulting from loss of the thiocarbonyl group, are systematically observed coproducts. In cases where the reductive alkylation reaction affords a poor yield, 4 may be produced in extensive amounts and even become the major product. For instance, starting from the “bad” substrates 1g−l, the corresponding amines 4h−l are produced in 20−58% yield. A straightforward explanation for the formation of these undesired compounds is a direct attack of the Grignard reagent at the carbon atom of the thiocarbonyl group. This is supported by the presence of the methyl ketone 5 resulting from hydrolysis of the tetrahedral intermediate G (Scheme 4), and the stench detected during workup of the reactions is consistent with the production of H2S. However, experimental evidence suggests that this is not the only pathway leading to 4, as the observed amount of 5 is uniformly lower than the quantity of 4. For instance, while 4h is produced in 58% yield from 1h using cyclohexylmagnesium chloride in tBuOMe, only a 15% yield of cyclohexyl methyl ketone is detected in the crude product. Moreover, as already mentioned, the thioamide 1a is left essentially unreacted when MeMgBr is used as the Grignard reagent under the standard conditions in THF. Only a 3% yield of amine 4a is produced in this reaction.

Scheme 4. Possible Competitive Pathways Leading to the Formation of the Amine Byproducts 4

Another possibility resides in the aerobic oxidation of the final intermediate D at the stage of the workup, instead of protonolysis. This would lead to the peroxide species I via a radical mechanism. Such oxidations of C(sp3)−Ti bonds into C−O bonds have been reported,10 and in the present study the formation of dimers in some cases is consistent with the generation of a radical H at the α position relative to the nitrogen atom (vide infra).11 The production of 4 by final hydrolysis of remaining unreacted intermediate B or C was also envisaged, but this hypothesis was invalidated by a complementary experiment (see Table 7, entry 10). Rotamers. Thioamides are known to have a larger rotational barrier than the corresponding carboxylic amides.12 Two batches of crystalline thioformamide 1b were synthesized: 5646


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Scheme 5. Reactions of N-(4-Chlorobutyl)thiolactam 1r

Scheme 6. Reaction of 1b Using Cyclohexylmagnesium Chloride with a D2O Quench at Low Temperature

Figure 2. 1H NMR spectra of (top) 2bb and (bottom) 2bb-d. The presence of two diastereoisomers of the latter compound, in approximately equimolar amounts, is clearly shown by the splitting of the quartet signal (CH, gold color) and of the AB system (CH2, green color) as well as by the two distinct CH doublet signals (salmon-pink color) instead of the AB part of an ABX system in the case of the nondeuterated molecule.

intramolecular SN2 reaction of 2rc after the workup of the reaction, at the stage of the concentration of the crude product by rotavapor distillation at 40 °C. Indeed, in another experiment conducted using n-propylmagnesium chloride, this transformation could be completely suppressed by the addition of HCl into the solution just before rotavapor distillation. The hydrochloride thus formed (2rd·HCl) could then be converted into the corresponding spirocyclic quaternary ammonium salt 6rd by simple stirring in tBuOMe in the presence of NaOH. In addition, from a mechanistic point of view, the same titanacyclopropane intermediate complex A1 (Scheme 1) is expected to be formed from isopropylmagnesium chloride and from n-propylmagnesium chloride. The fact that two different products, the isopropyl- and n-propyl-substituted molecules 6rc

one consisting of a 72:28 mixture of rotamers and the other containing a single rotamer. Having verified that the isomerization of these rotamers is slow in solution,13 we compared the results of reactions performed on the two batches. The difference of behavior was found to be minor. The reductive alkylation process is perhaps slightly more efficient starting from the single rotamer, with somewhat less dibenzylamine (4b) being produced.9 Special Case of the N-(4-Chlorobutyl) Substrate 1r. When the standard protocol is used with isopropylmagnesium chloride, the product isolated from thiolactam 1r is not the corresponding tertiary amine 2rc but instead is the spirocyclic quaternary ammonium salt 6rc (Scheme 5). The experimental evidence indicates that this molecule is formed by an 5647


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beneficial (entry 8). Nonetheless, the 70% yield achieved for the transformation of 1b into 2bb constitutes a significant improvement over our initial result. The same kind of positive effect has been observed recently in several cases of intramolecular cyclopropanation reactions, performed under similar conditions, starting from N-alkenyl thioamides.7 Amounts of Ti(OiPr)4 and Grignard Reagent. On the basis of the mechanisms put forward in Schemes 1 and 2, the quantitative formation of the reductive alkylation product 2 requires 1 equiv of A and 1 equiv of Grignard reagent. Therefore, n ≥ 1 mmol of Ti(OiPr)4 and p ≥ 2n + 1 mmol of Grignard reagent should be engaged per millimole of 1. Various combinations complying with this rule were explored starting from the substrates 1a, 1b, and 1e in THF with cyclohexylmagnesium chloride as the Grignard reagent (Table 5). Two reactions of 1b were also run with a smaller amount of Ti(OiPr)4 (entries 5 and 6; vide infra). In full agreement with

and 6rd, are exclusively obtained using the corresponding Grignard reagents provides convincing evidence that the organometallic species attacking the metalated iminium intermediate Cr is not A1. Further Studies. On the basis of the first set of results, further experiments were conducted with the aims of extending the possibilities offered by the reductive alkylation reaction, improving its efficiency, and gaining new insight into the mechanistic pathways involved. Several topics were investigated and are discussed hereafter. Trapping of the Final Intermediate. The presence of a carbon−metal bond in the proposed final intermediate D (Scheme 2) is supported by the results of reactions quenched with D2O. When cyclohexylmagnesium chloride was used as the Grignard reagent with the thioamides 1a, 1b, and 1n, the corresponding deuterated amines 2ab-d6, 2bb-d, and 2nb-d were synthesized with ∼90% deuterium incorporation. The case of 2bb-d is interesting because two diastereoisomers of this molecule may be produced. In practice, the diastereoisomeric ratio was found to be close to 50:50, even when the addition of D2O was performed at −70 °C (Scheme 6 and Figure 2). If it is assumed that the deuteriolysis of the final intermediate Dbb proceeds with retention of configuration, this result can be explained by poor diastereoselectivity of the Grignard reagent addition onto the zwitterionic intermediate complex Cb and/or by configurational instability of Dbb. In another experiment, the formation a carbon−carbon bond from Dab was attempted using benzaldehyde as an electrophilic trap (75 min at 20 °C then 30 min at reflux of THF). However, the formation of the anticipated amino alcohol product was not observed. The major product was still the reductive alkylation adduct 2ab (44% yield), suggesting that the nucleophilicity of the complex Dab is not sufficient for it to react with benzaldehyde. A similar negative result was obtained starting from the thioacetamide 1e. Other reactions were attempted without success: with an activated Michael acceptor, with the radical trap TEMPO, with anisaldehyde in the presence of CuBr2, and with allyl bromide in the presence of CuCN·2LiCl.9 Rate of Addition of the Grignard Reagent. The influence of the rate of addition of the Grignard reagent was briefly examined using cyclohexylmagnesium chloride, starting from the substrates 1a and 1b in THF (Table 4). In both cases, an addition time of about 2 h consistently gave better results than a 5−30 min addition (entry 3 vs entries 1 and 2 and entry 7 vs entry 4). It should be pointed out that the magnitude of this effect is moderate, and further reducing the addition rate is not

Table 5. Effect of the Amounts of Ti(OiPr)4 and cC6H11MgCl on the Reactions of 1a, 1b, and 1ea entry substrate 1 2 3 4 5 6 7 8 9 10 11 12

substrate

product

addition time (min)

yieldb

1 2 3 4 5 6 7 8

1a

2ab

1b

2bb

7 28 110 7 30 60 110 260

51% 54% (43%) 55% 58% 59% 64% (55%) 66−70% 63%

1a

2ab

1b

2bb

1e

2eb

mmol of cC6H11MgCl per mmol of 1

yieldb

1.25 1.5 1.5 1.5 0.5 0.75 1.0 1.0 1.5 1.5 1.2 1.5

4.0c 4.0c 4.3c 5.0c 4.0d 4.0d 3.0d 4.0d 4.0d 4.5d 4.0e 4.0e

44% 46−48% 54% (43%) 55% 14% 55% 36% 65% 70% 66% 39%f 37%g

a Reactions were run in THF, unless otherwise stated. bYields estimated by NMR analysis of the crude products. The yield in parentheses is for the isolated product. cThe Grignard reagent was added over 26−45 min. dThe Grignard reagent was added over 100− 120 min. eThe Grignard reagent was added over 7−8 min. f31% yield in tBuOMe or Et2O; 34% yield in cC5H9OMe. g43−48% yield in tBuOMe.

the proposed mechanism, with 1.5 mmol of Ti(OiPr)4/mmol of 1, little change in the yield is observed when the amount p of the Grignard reagent is varied in the interval ranging from 4.0 to 5.0 mmol/mmol of 1 (entries 2−4, 9, and 10). Moreover, when the value of p is fixed at 4.0 mmol/mmol of 1, the effect of a reduction of the amount n of Ti(OiPr)4 to 1.25, 1.2, or even 1.0 mmol/mmol of 1 is marginal as well (entry 1 vs entry 2, entry 8 vs entry 9, and entry 11 vs entry 12). However, when n is further reduced to 0.75 and down to 0.5 mmol/mmol of 1, the conversion is not complete and the yield of 2bb decreases dramatically (55% and 14%, respectively, vs 65% with n = 1.0; entries 5 and 6 vs entry 8). This is again consistent with the proposed mechanism, since an insufficient quantity of the intermediate A3 would then be generated. It should also be noted that with the theoretical minimal amounts of reagents (n = 1.0 and p = 3.0 mmol/mmol of 1), an unsatisfactory 36% yield is obtained (entry 7). In contrast, rather unexpected results were observed when more “irrational” proportions of reagents were engaged (Table 6). In particular, the results presented in entries 4 and

Table 4. Influence of the Rate of Addition of the Grignard Reagenta entry

product

mmol of Ti(OiPr)4 per mmol of 1

a

Reactions were run in THF using 1.5 equiv of Ti(OiPr)4 and 4.0−4.5 equiv of cC6H11MgCl. bYields estimated by NMR analysis of the crude product. Yields in parentheses are for the isolated products. 5648


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Table 6. Reactions Run with Unusual Proportions of Reagents Compared with Reactions Performed under the Standard Conditionsa entry

substrate

product

reagents (mmol per mmol of 1)

yieldb

drb

1

1e

2eb

Ti(OiPr)4 (1.5) cC6H11MgCl (4.0) Ti(OiPr)4 (2.0) cC6H11MgCl (4.0) Ti(OiPr)4 (1.5) cC6H11MgCl (4.0) Ti(OiPr)4 (2.4) cC6H11MgCl (3.6) Ti(OiPr)4 (1.5) iPrMgCl (4.0) Ti(OiPr)4 (3.0) iPrMgCl (4.5)

43−48% (30%)

−

48%c

−

2 3

1o

2ob

4 5 6

1o

2oc

81% (51%)

68:32

69%d

75:25

79%

67:33

57%e

74:26

a

Reactions were run in tBuOMe. The Grignard reagent was added within 5−8 min in each case. bYields and diastereomeric ratios (dr) estimated by NMR analysis of the crude products. Yields in parentheses are for the isolated products. cN,N-Dibenzylamine (22%) and starting material (19%) were also observed in the crude product. d21% unreacted starting material 1o was detected in the crude product. e32% 1o was detected in the crude product.

Scheme 7. Simplified Mechanistic Proposition Explaining the Reductive Alkylation of 1 When Ti(OiPr)4 and the Grignard Reagent Are Employed in a 2:3 Ratio

With respect to the titanium(IV) alkoxide reagent, ClTi(OiPr)3 led to a comparatively good result in the synthesis of the amine product 2ab. This compound was formed in 57% yield from 1a, compared with 51% using Ti(OiPr)4 under otherwise identical conditions (Scheme 8 top). This is the best

6 were obtained using a 2:3 ratio of Ti(OiPr)4 and Grignard reagent RMgX. Under these conditions, an equimolar amount of A and organotitanium species RTi(OiPr)3 J are expected to be produced (Scheme 7), and the addition of a significant amount of Grignard reagent onto the metalated iminium intermediate complex C is unlikely.14 Nonetheless, although the conversion is not complete, the reductive alkylation process remains efficient and the diastereoselectivity of the formation of 2ob and 2oc is improved (entries 4 and 6 vs entries 3 and 5). These results can readily be understood if it is the alkyltitanium complex J rather than the Grignard reagent that attacks the zwitterionic intermediate species C. Complementary experiments presented in the next two subsections strongly support the validity of this hypothesis. Since complexes such as J are expected to be moderately nucleophilic, some activation may operate, for instance via a transition state such as K (Scheme 7).15 The formation of an intermediate ate complex, where the negatively charged sulfur atom of C would coordinate to the metal center of J before intramolecular delivery of the alkyl group, could be proposed as well. Other Reagent Systems. Replacement of the Grignard reagent with an organolithium reagent was briefly examined. After 1a was treated with Ti(OiPr)4 (1.5 equiv) and nBuLi (4.0 equiv) in THF, only small amounts of the expected alkylation product N,N-dibenzylpentylamine (2af) were detected, and the main reaction product was N,N-dibenzylamine, isolated in 56% yield. Such reaction conditions are thus not suitable.

Scheme 8. Comparison of the Reactions of 1a using Ti(OiPr)4, ClTi(OiPr)3, MeTi(OiPr)3, and Me2Ti(OiPr)2 Generated in Situ

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yield achieved to date for this reaction. In contrast, in the case of the synthesis of 2fb from 1f, a run using Cl2Ti(OiPr)2 instead of Ti(OiPr)4 in tBuOMe led to a more complex mixture of products and a reduction in the yield from 47 to 33%. A particularly interesting alternative to the use of Ti(OiPr)4 is MeTi(OiPr)3, as put forward and demonstrated by de Meijere and co-workers.3c,16,17 Indeed, while the formation of the key titanacyclopropane intermediate A3 from Ti(OiPr)4 requires the consumption of 2 equiv of cC6H11MgCl, the same species can in principle be generated from MeTi(OiPr)3 using 1 equiv of cC6H11MgCl. In the present case, employing MeTi(OiPr)3 seemed an attractive way of proving that alkyl(triisopropyloxy)titanium complexes J can alkylate the intermediate C. Indeed, the amine 2ae resulting from reductive methylation is obtained as the major product from 1a, albeit with low conversion (Scheme 8 middle). Another experiment, run by adding cC6H11MgCl to a preformed equimolar mixture of MeTi(OiPr)3 and Me2Ti(OiPr)2 in the presence of 1a, leads to an improved result, suggesting that Me2Ti(OiPr)2 can also add efficiently onto Ca (Scheme 8 bottom). Extension to the Introduction of Other Nucleophiles. Finally, the more general possibility of controlling the formation of the putative key zwitterionic intermediate C in order to trap it with various nucleophiles was investigated. A potential problem was an attack on this metalated iminium species, in the course of its generation, by the organotitanium intermediate complex J (see Scheme 7). Since our results suggested that this process is slower in THF than in tBuOMe and also slower at 0 °C than at 20 °C, the best chances of success seemed to lie in the use of THF at low temperature. Good and reliable results are indeed obtained using 1.5 equiv of Ti(OiPr)4 and 3.0 equiv of cyclohexylmagnesium chloride added at −30 °C in THF, with the reaction mixture being allowed to warm to 0 °C over a 30 min period prior to trapping with several nucleophiles (Table 7).18 As expected, the following order is observed for the introduction of a methyl group: MeLi > MeMgBr > MeTi(OiPr)3 (entries 1−5). Notwithstanding the low yield obtained with the last of these reagents (35%), its ability to add onto the species Ca is demonstrated unequivocally. It is interesting to note that, as anticipated, the addition of MeTi(OiPr)3 is more facile in tBuOMe than in THF (entry 5 vs entry 4). Presumably the transition state K can be reached more easily in the lesscoordinating solvent tBuOMe. In contrast, with MeLi, a better result is obtained in THF than in tBuOMe (68%, entry 1 vs 44%, entry 2). With PhLi, the dimeric diamine 3ah is produced almost exclusively (entry 7). This perhaps surprising result is discussed in the next subsection. A hydride or deuteride anion can also be delivered using LiAlH4 or LiAlD4 (entries 8 and 9). In contrast, the following reagents proved unsuitable: NaBD4, 2-phenylethynyllithium, 1-phenylvinyloxylithium, vinylmagnesium bromide (with or without subsequent trapping with anisaldehyde), (trifluoromethyl)trimethylsilane (in the presence or absence of nBu4NF), phenol, and diethyl malonate deprotonated with NaH. Rather surprisingly, extensive amounts of starting material 1a were observed in several of these cases.9 An experiment involving the direct aqueous workup of a solution of Ca was then carried out. The crude product contained essentially pure 1a (entry 10). Further work is needed to fully understand this result and the overall reactivity of the putative species Ca, but it appears that no reaction (or a very slow one) takes place with water and decomplexation eventually occurs,

Table 7. Extension to the Generation and Trapping of the Metalated Iminium Complex Ca

a Unless otherwise stated, the reactions were run in THF. bYields estimated by NMR analysis of the crude products. Yields in parentheses are for the isolated products. cThis reaction was run in tBuOMe. dThe substrate 1a was the main component of the crude product (90−93%). eA small amount of amine 2ah (4%) was also observed. 3ah was produced as a 57:43 meso/dl mixture of diastereoisomers. Only the meso compound was isolated. fThe reaction was quenched with D2O. Deuterium incorporation: 71% d2, 26% d1, 3% d0. gThe hydrolysis was carried out on half of the reaction mixture. The other half was successfully reacted with LiAlH4 to produce 2ai. h55:45 dr (measured in the crude product). icC6H11MgCl was added at 0 °C over 6 min, and MeLi was then added after 2 min of stirring at 0 °C. 57:43 dr (measured in the crude product).

probably from Ba, which is assumed to be in equilibrium with Ca. It is also interesting to note that no trace of the cyclohexylcontaining amine 2ab is produced under these conditions. The selectivity of the nucleophilic addition process is good in several cases, with 2ab being produced as a very minor side product (less than 7% yield; entries 1, 5, and 7−9). The result of the reaction with water discussed above (entry 10) suggests that 2ab is formed after the introduction of the nucleophilic reagent, presumably when the reaction mixture is allowed to warm to 20 °C. However, starting from the thiolactam substrate 1q, the formation of rather large amounts (20%) of cyclohexyl byproduct 2qb is not avoided (entries 11 and 12). A solution to this problem, in this particular case, consists of adding 3.0 equiv of MeLi at 0 °C to a THF solution of 1q and cC6H11Ti(OiPr)3 (generated in situ from 1.5 equiv of Ti(OiPr)4 and 1.5 equiv of cC6H11MgCl at −10 °C). Under these conditions, the production of 2qb is suppressed and the yield of 2qe is not affected.9 The absolute configuration of the carbon center bearing the newly introduced methyl group, on the slightly major diastereoisomer, is assigned as S on the basis of literature data.19 An additional experiment aimed at quickly evaluating the generation of Cb from 1b by ligand exchange from A (R = Et), preformed by the reaction of 2.0 equiv of Ti(OiPr)4 with 3.6 5650


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equiv of nBuLi in THF at 0 °C,20,21 gave an unsatisfactory result after trapping with cyclohexylmagnesium chloride: the expected product 2bb was formed in 35% yield but was accompanied by the production of the n-pentylamine derivative 2bf in 18% yield. Formation of Dimers. The unexpected dimeric compounds 3cb and 3ah are both produced as a mixture of two diastereoisomers. The major diastereoisomer of 3ah was shown to be the meso molecule by X-ray crystallography (Figure 3). These products are likely to result from

radical species from the intermediates Dcb and Dah is thus comparatively much more favorable thermodynamically than in the general situation, and their dimerization is also especially plausible. In an attempt to ascertain whether 3cb could be formed at the stage of the workup of the reaction mixture through a pathway in which the radical Lcb would be generated after single electron transfer from oxygen to Dcb, an experiment was conducted in which the aqueous workup was preceded by exposure of the reaction mixture to dry air for 30 min. Under these conditions, the yield of the “normal” reductive alkylation product 2cb dropped drastically from 33 to 5%, which is consistent with the consumption of the final intermediate Dcb and the generation of the radical Lcb. However, no increase in the amount of 3cb was observed,23 and a new compound was produced. Although the latter could not be isolated and has not been unequivocally identified, it is reasonable to assume that it is the hydroperoxide resulting from trapping of Lcb by molecular oxygen.24 This result suggests that the diamines 3cb and 3ah are formed before the workup of the reaction mixture. It is worth pointing out that similarly stabilized radicals could be generated in reactions performed from the substrates 1i and 1k, although the corresponding dimeric diamine products were not observed. It is reasonable to assume that if formed, these radicals would add intramolecularly onto the neighboring alkene group, resulting in the production of other compounds that were not identified.

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CONCLUSIONS The reductive alkylation of thioamides 1 by Grignard reagents in the presence of Ti(OiPr)4 is a fairly general reaction. The main limitations of this transformation are the necessity to use a tertiary thioamide and, in the simplest version of the reaction, a Grignard reagent having hydrogen atoms at the β position. However, the yields are often rather moderate or low. Our new investigations show that improved results can be achieved and that the parameters especially worth considering for optimization are the choice of the solvent, the nature of the titanium(IV) reagent, in particular ClTi(OiPr)3 instead of Ti(OiPr)4, and the rate of addition of the Grignard reagent. From a mechanistic point of view, although our initial proposition proved to be essentially correct, the actual picture is more complicated, with a rich variety of possible pathways. All of our results are consistent with the initial generation of a titanacyclopropane complex A, as widely accepted when such a combination of reagents is engaged. A ligand exchange process with the thiocarbonyl group leads to the formation of the metalated iminium species C. This complex behaves as a moderately electrophilic reagent that has been demonstrated to react with LiAlH 4 , alkyllithium, alkylmagnesium, and alkyltitanium(IV) reagents. In particular, as C is being gradually generated, trapping by the first intermediate RTi(OiPr)3 produced by the reaction of RMgX with Ti(OiPr)4 can be a significant pathway, notably in tBuOMe. This process is believed to involve coordination of RTi(OiPr)3 by the sulfur atom of C. Depending on the conditions applied, in particular the proportions of the reagents, the actual reaction pathway is thus flexible. When MeTi(OiPr)3 is used rather than Ti(OiPr)4, the reaction can even be diverted toward the formation of reductive methylation products that were not accessible initially. Moreover, by reducing the amount of Grignard reagent

Figure 3. Single-crystal X-ray diffraction structure of the major meso diastereoisomer of 3ah. Ellipsoids are displayed at the 50% probability level.

dimerization of the radicals Lcb and Lah generated by homolysis of the carbon−titanium bond of the corresponding intermediates Dcb and Dah (Scheme 9). Although the mechanism of such a homolysis event is not clear (e.g., under the action of light22 or after single-electron oxidation or attack by a heteroatom-centered radical), one can point out that the radicals Lcb and Lah are stabilized by resonance; Lah is even stabilized by the captodative effect. The generation of these Scheme 9. Proposed Pathway Leading to Diamines 3

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General Procedure for the Generation of the Intermediate Complex C, Followed by Trapping with a Nucleophilic Reagent. Ti(OiPr)4 (1.5 mmol/mmol of 1) is added to a stirred solution of thioamide substrate 1 in the reaction solvent (v mL). The Grignard reagent (p mmol/mmol of 1) is then introduced (typically at −30 °C) over 3−7 min. During the addition, the solution typically turns yellow. The reaction mixture is then allowed to warm to 0 °C over 30 min (orange color). The nucleophilic reagent (typically 1.5 mmol/mmol of 1) is added at 0 °C. After 5 min the cold bath is removed, and the reaction mixture is stirred at 20 °C for 60 min. Then 25% NH3 aqueous solution (0.50 mL/mmol of substrate) is added, and after 30 min of stirring (the formation of a white precipitate is observed), the mixture is exposed to air and filtered through a short pad of sand, Na2SO4, Celite, and sand (from bottom to top), rinsing with Et2O. The resulting clear solution is concentrated under reduced pressure to afford the crude product. The latter is analyzed by NMR spectroscopy and the products are typically isolated by flash column chromatography. Typically, the solvent is THF (v = 10), the Grignard reagent is cC6H11MgCl (p = 3.0) and is added at −30 °C. The reactions were performed starting from 0.50 to 1.0 mmol of 1.

employed and by controlling the temperature, it is possible to selectively generate the above-mentioned metalated iminium intermediate C, which can then react with a nucleophile introduced at this stage. This represents a substantial extension of our original method. The final α-metalated amine intermediate D behaves as a base but does not exhibit nucleophilic properties. However, it can play the role of a radical precursor. In particular, when the corresponding radicals are sufficiently stabilized, diamines resulting from dimerization of these species can be produced. Another possible reaction that was observed experimentally is the formation of hydroperoxide compounds by aerobic oxidation of D. Future work on this topic in our laboratory will be devoted to new extensions of the reductive alkylation reaction and further elucidation of some aspects of this chemistry.

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EXPERIMENTAL SECTION

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General Information. Titanium(IV) isopropoxide (VERTEC TIPT) was purchased from Alfa Aesar, distilled under reduced pressure, and stored under nitrogen for several months. The Grignard reagents (methylmagnesium bromide, n-propylmagnesium chloride, isopropylmagnesium chloride, tert-butylmagnesium chloride, cyclopentylmagnesium chloride, and cyclohexylmagnesium chloride) were purchased from Sigma-Aldrich or Acros as solutions (typically ∼2 M in Et2O) and titrated once a month according to methods described earlier.10e,25 The organolithium reagents (methyllithium, n-butyllithium, sec-butyllithium, and phenyllithium) were purchased from Sigma-Aldrich or Acros as solutions (typically 1.7−2.5 M in hexanes) and titrated once a month according to literature methods.25,26 Other commercial reagents were used as received without purification. Tetrahydrofuran, diethyl ether, toluene, and dichloromethane were purified using an MB SPS-800 solvent purification system (MBRAUN). tert-Butyl methyl ether and cyclopentyl methyl ether were purchased from Acros or Alfa Aesar and used as received. Petroleum ether refers to the 40−60 °C fraction. This and all of the other solvents were purchased from VWR and used without purification. All of the reactions were carried out under a stream of nitrogen or argon, unless specified otherwise. The temperatures mentioned are the temperatures of the cold baths used. Concentration under reduced pressure was carried out using rotary evaporators at 40 °C. Flash column chromatography was performed on Merck silica gel 60 (40−63 μm). NMR spectra were recorded with Bruker AM 400 and AVANCE 400 spectrometers (1H at 400.2 MHz, 13C at 100.6 MHz). Infrared spectra were recorded with a PerkinElmer 2000 FT-IR spectrometer. Melting points were determined using a Büchi 535 apparatus. Low-resolution mass spectra were recorded on a HewlettPackard Quad GC−MS engine spectrometer via direct injection. Highresolution mass spectrometry was performed on a JEOL GCmate II spectrometer. General Procedure for the Reductive Alkylation of Thioamides. The alkoxytitanium(IV) reagent (n mmol/mmol of 1) is added to a stirred solution of thioamide substrate 1 (typically 0.50−1.0 mmol) in the reaction solvent (v mL/mmol of 1). The Grignard reagent (p mmol/mmol of 1) is then added at 0 °C over a time t. The cold bath is removed, and the reaction mixture is stirred at 20 °C for a time T. After this time, 25% NH3 aqueous solution (0.50 mL/mmol of substrate) is added. After 30 min of stirring (the formation of a white precipitate is observed), the mixture is exposed to air and filtered through a short pad of sand, Na2SO4, Celite, and sand (from bottom to top), rinsing with Et2O. The resulting clear solution is concentrated under reduced pressure to afford the crude product. The latter is analyzed by NMR spectroscopy. The products are typically isolated by flash column chromatography. Typically, the alkoxytitanium(IV) reagent is Ti(OiPr)4 (n = 1.5), p = 4 for the Grignard reagent, the solvent is tBuOMe or THF (v = 10 to 20), t ranges from a few to 120 min, and T is 60 min.

ASSOCIATED CONTENT

* Supporting Information S

Experimental procedures, additional results, characterization data and spectra, and crystallographic data (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Fax: (+33) (0)1 6933 5972. E-mail: yvan.six@polytechnique. edu. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We warmly thank Ewelina Augustowska, Antoine Boiron, Jérôme Deffit, Natalia Szwankowska, Aleksander Przybyła, Kamila Piotrowska, and Natalia Witkowska for their contributions to this work. We are also grateful to Michel Levart for the MS analyses of our compounds and to the École Polytechnique for financial support, in particular for the research grant attributed to F.H. Funding from the CNRS is also acknowledged. Finally, Y.S. especially thanks Prof. S. Z. Zard for his continuous encouragement and valuable support.

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REFERENCES

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Chem. 2001, 624, 229−238. (c) Eisch, J. J.; Owuor, F. A.; Otieno, P. O. Organometallics 2001, 20, 4132−4134. (22) Cp2TiCl2 undergoes homolysis of a C−Ti bond when exposed to UV irradiation. See: Brindley, P. B.; Davies, A. G.; Hawari, J. A.-A. J. Organomet. Chem. 1983, 250, 247−256 and references cited therein. (23) However, it must be said that the solubility of the dimers 3cb and 3ah in common solvents is low, which certainly affects the accuracy of the yields obtained and tends for them to be underestimated. (24) The 1H NMR signals assigned to this compound disappeared when NaBH(OAc)3 was added to a CDCl3 solution of a crude product where it had been identified as a constituent. See the Supporting Information for further details. (25) Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503− 2506. (26) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879− 1880.

Gazizova, V.; Savchenko, A. I.; Boese, R.; Schill (née Brackmann), F. Chem.Eur. J. 2010, 16, 13862−13875. (4) Initial report: (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792−1793. Dedicated review: (b) Bertus, P.; Szymoniak, J. Synlett 2007, 1346−1356. (5) Initial reports: (a) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203−3206. (b) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 3207−3210. (c) Urabe, H.; Hata, T.; Sato, F. Tetrahedron Lett. 1995, 36, 4261−4264. Reviews: (d) Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000, 753−775. (e) Sato, F.; Okamoto, S. Adv. Synth. Catal. 2001, 343, 759−784. (f) Reichard, H. A.; Micalizio, G. C. Chem. Sci. 2011, 2, 573−589. (6) Augustowska, E.; Boiron, A.; Deffit, J.; Six, Y. Chem. Commun. 2012, 48, 5031−5033. (7) Hermant, F.; Nicolas, E.; Six, Y. Tetrahedron 2014, 70, 3924− 3930. (8) Selected examples: (a) Savchenko, A. I.; Kulinkovich, O. G. Zh. Org. Khim. 1997, 33, 913−915; Russ. J. Org. Chem. 1997, 33, 846−848. (b) Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem. 2002, 114, 2264−2266; Angew. Chem., Int. Ed. 2002, 41, 2160−2162. (c) Isakov, V. E.; Kulinkovich, O. G. Synlett 2003, 967−970. (d) Lysenko, I. L.; Kim, K. K.; Lee, H. G.; Cha, J. K. J. Am. Chem. Soc. 2008, 130, 15997−16002. (e) Bobrov, D. N.; Kim, K.; Cha, J. K. Tetrahedron Lett. 2008, 49, 4089−4091. (f) Madelaine, C.; Ouhamou, N.; Chiaroni, A.; Vedrenne, E.; Grimaud, L.; Six, Y. Tetrahedron 2008, 64, 8878−8898. (g) Astashko, D.; Lee, H. G.; Bobrov, D. N.; Cha, J. K. J. Org. Chem. 2009, 74, 5528−5532. (h) Astashko, D.; Cha, J. K.; Rao, N. N.; Parida, B. B. Eur. J. Org. Chem. 2014, 181−187. (9) See the Supporting Information for details. (10) Especially relevant examples: (a) Nakamura, E.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc. 1986, 108, 3745−3755. (b) Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1997, 119, 8127−8128. (c) Sung, M. J.; Lee, C.-W.; Cha, J. K. Synlett 1999, 561−562. (d) Six, Y. J. Chem. Soc., Perkin Trans. 1 2002, 1159−1160. (e) Six, Y. Eur. J. Org. Chem. 2003, 1157−1171. (f) Cadoret, F.; Retailleau, P.; Six, Y. Tetrahedron Lett. 2006, 47, 7749−7753. (11) Moreover, experiments conducted in the frame of the present study, where dry air was introduced at the end of the reaction of the thioamide 1c, strongly support the hypothesis of the aerobic oxidation of Dc into a peroxide compound (see the Supporting Information for details). For this reason, we recommend maintaining the nitrogen (or argon) flow during the aqueous workup of the reactions. (12) Wiberg, K. B.; Rablen, P. R. J. Am. Chem. Soc. 1995, 117, 2201− 2209 and references therein. (13) As evaluated by NMR spectroscopy in CDCl3 solution at 20 °C, the rotamer ratio changes from 100:0 to 96:4 after 2 h. After total times of 4 and 8 h, it becomes 93:7 and 88:12, respectively. (14) For other applications of the use of Ti(OiPr)4 and a Grignard reagent in a similar ratio, see: (a) Reference 10f. (b) Cadoret, F.; Six, Y. Tetrahedron Lett. 2007, 48, 5491−5495. Also see: (c) Lack, O.; Martin, R. E. Tetrahedron Lett. 2005, 46, 8207−8211 (2 equiv of MeTi(OiPr)3 and 1 equiv of EtMgBr). (15) With the standard procedure and proportions of reagents, it is not excluded that the addition of the Grignard reagent onto C proceeds via an analogous transition state. (16) (a) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere, A. Synlett 1997, 111−114. (b) de Meijere, A.; Winsel, H.; Stecker, B. Org. Synth. 2005, 81, 14−25. (17) Also see: Lee, J. C.; Sung, M. J.; Cha, J. K. Tetrahedron Lett. 2001, 42, 2059−2061. (18) Performing the reaction entirely at 0 °C gives somewhat inferior results, and so does the use of tBuMgCl instead of cC6H11MgCl (see the Supporting Information for details). (19) Nugent, T. C.; Ghosh, A. K. Eur. J. Org. Chem. 2007, 3863− 3869. (20) Rassadin, V. A.; Six, Y. Tetrahedron 2014, 70, 787−794. (21) This combination of reagents was introduced by Eisch and coworkers. See: (a) Eisch, J. J. J. Organomet. Chem. 2001, 617−618, 148− 157. (b) Eisch, J. J.; Gitua, J. N.; Otieno, P. O.; Shi, X. J. Organomet. 5653


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