JACS-炔烃和醛的区域可调控的加成反应

Regiocontrol in Catalytic Reductive Couplings through Alterations of Silane Rate Dependence

Evan P. Jackson and John Montgomery *

Department of Chemistry, University of Michigan, 930North University Avenue, Ann Arbor, Michigan 48109-1055, United States

Supporting Information *

Reductive couplings of two π-components have been widely developed for numerous substrate combinations utilizing many transition metals across the periodic table. 1,2Numerous highly e ﬀective processes have been described that provide control of both regiochemistry, stereoselectivity, and enantioselectivity across a broad range of substrates, but the ability to reverse the regiochemical biases inherent to a particular substrate class is still quite challenging and rare. 3As a result, most regioselective reductive coupling processes employ electronically or sterically biased π-components that naturally favor a single regioisomer. In these cases, access to the opposite regioisomer without modi ﬁcation of the substrate typically cannot be achieved. In the rare cases where regiochemical reversal may be achieved, the most commonly employed strategies involve (a)special alkyne structures that allow directed additions, where the directing e ﬀect may be turned on and o ﬀby ligands employed, or (b)ligand structures that allow access to either product regioisomer through the development of steric interactions in the oxidative cyclization step.

The nickel-catalyzed reductive coupling of aldehydes and alkynes is a representative reaction class where regiochemical reversals have been demonstrated by these two strategies. 4In alkene-directed reactions reported by Jamison, the ligand environment on nickel may be tuned to allow the directing group either to complex the catalyst or be e ﬀectively displaced by altering the ligand structure and concentration. By this strategy, the regiochemical outcome may be reversed. 5In work from our laboratory, rate-determining formation of an oxametallacyclic intermediate is highly sensitive to ligand sterics, and regiochemistry reversals may be directly observed across a range of substrates simply by ligand alteration. 6Computational studies from Houk have been conducted on both of these nickel-catalyzed methods, and signi ﬁcant insight

provided. 7

Irrespective of strategy employed, the mechanism in all of the prior work on nickel-catalyzed aldehyde −alkyne reductive couplings appears to involve oxidative cyclization of a Ni(0)−aldehyde −alkyne complex 1to form a ﬁve-membered metal-lacycle 2as the rate-and regiochemistry-determining step (Scheme1). σ-Bond metathesis of the silane with the Ni −O bond of 2then a ﬀords intermediate 3in a fast reaction that follows rate-determining metallacycle formation, and reductive elimination of 3then provides the observed silyl-protected Scheme 1. Mechanism of Prior

Protocols

Received:November 16, 2014

allylic alcohol product. Both detailed kinetics studies and computational studies have provided evidence in support of this generalization. 7,8

As would be expected for a sequence involving rate-and regiochemistry-determining oxidative cyclization, silane struc-ture and concentration generally has no e ﬀect on the regioselectivity outcome. Whereas ligand control or directing group e ﬀects in ﬂuence the regioselectivity outcome, the involvement of silane structural in ﬂuences on the σ-bond metathesis step has not been developed as a regiocontrol strategy. Herein, we disclose that an interplay of silane structure, ligand structure, and temperature leads to alteration of the kinetic behavior of this system, and the insights provide a new strategy for regiochemistry reversals in this class of reactions.

RESULTS AND DISCUSSION

Experimental Factors That In ﬂuence Regioselectivity. The nickel-catalyzed coupling of benzaldehyde with phenyl propyne has been reported with a broad range of protocols. Using the most widely used phosphines (i.e.,PCy 3) or N -heterocyclic carbene ligands (i.e.,IMes), near-perfect regiose-lectivities for structure 6are typically observed irrespective of reducing agent employed, including a broad range of silanes or Et 3B (whichprovides the free hydroxyl of 6). The outcomes of couplings using IMes or SIMes as ligand with Et 3SiH or (i -Pr) 3SiH as the reductant are provided as representative examples (Table1, entries 1−4). In these cases, highly regioselective production of 6was observed with no in ﬂuence of silane structure on regioselectivity. Couplings using the bulkier ligand IPr provided nearly equivalent quantities of regioisomers 5and 6, and a small in ﬂuence of the silane structure was noted (Table1, entries 5and 6). However, Table 1. Ligand and Silane Structural E ﬀects

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couplings using SIPr as ligand surprisingly displayed a much more pronounced in ﬂuence on silane structure (Table1, entries 7−11). With SIPr as ligand, couplings proceeded in 58:42regioselectivity with Et 3SiH, whereas increasing the silane size resulted in an increase in regioselectivity up to >98:2selectivity favoring regioisomer 5with t -Bu 2MeSiH as reductant. This outcome provides a highly selective procedure that completely reverses the outcome seen with more typical protocols, which strongly prefer the production of regioisomer 6.

We initially rationalized this unexpected ﬁnding as potentially being derived from a change in rate-determining step, where metallacycle formation becomes reversible (i.e.,the 1to 2conversion, Scheme 1), 9and participation of the silane becomes rate-determining (i.e.,the 2to 3conversion, Scheme 1) as the silane size increases. This hypothesis further suggested additional opportunities for altering the relative rates of metallacycle formation and σ-bond metathesis, thus providing additional experimental handles for adjusting regiocontrol. For example, lowering the concentration of silane should slow the rate of the silane σ-bond metathesis while not a ﬀecting the rate of metallacycle formation, therefore favoring the pathway involving reversible metallacycle formation. Additionally, the previous computational studies illustrated a signi ﬁcant entropic penalty associated with the σ-bond metathesis step. 7c,d Such a penalty would be maximized at high temperature, suggesting that increasing temperature would provide another handle for favoring the reversible metallacycle formation pathway. Using the benchmark example of the benzaldehyde −phenylpropyne coupling process, we conducted a series of experiments to evaluate these hypotheses.

As expected for a protocol where metallacycle formation is rate-determining, the silane concentration should not a ﬀect the regiochemical outcome. Using the standard protocol with SIPr as the ligand and Et 3SiH as the reductant, this outcome was documented, where a 5-fold increase in silane concentration a ﬀorded identical outcomes in regioselectivity (Table2, entries 1and 2). However, a marked contrast was observed in reactions involving SIPr as ligand but utilizing a bulkier silane (i -Pr) 3SiH as reductant (Table2, entries 3−6). Characteristic Table 2. Concentration E ﬀects

entry [1**********]11

ligand IMes IMes SIMes SIMes IPr IPr SIPr SIPr SIPr SIPr SIPr

R 3SiH Et 3SiH (i-Pr) 3SiH Et 3SiH (i-Pr) 3SiH Et 3SiH (i-Pr) 3SiH Et 3SiH

t -BuMe 2SiH t -BuPh 2SiH (i -Pr) 3SiH (t -Bu) 2MeSiH

5:6(%yield)

4:96b 4:96b 44:56b 56:44b 58:42(65)60:40(83)77:23(86)83:17(89)>98:2(61)

entry 123456

silane (equiv)Et 3SiH (2.0)Et 3SiH (10.0)(i-Pr) 3SiH (1.1)(i-Pr) 3SiH (2.0)(i-Pr) 3SiH (10.0)(i-Pr) 3SiH (2.0)

conc b (M)0.1250.1250.1250.1250.1250.0125c

5:6(%yield) 58:42(65)58:42(32)95:5(57)83:17(89)68:32(93)>98:2(82)

Ni(COD)2(0.06mmol), ligand ·HCl (0.05mmol), and t -BuOK (0.05mmol) were stirred with 2mL of THF. Benzaldehyde (0.5mmol), phenylpropyne (0.5mmol), and silane (1.0mmol) were combined, diluted to a total volume of 2mL, and added to the reaction mixture via syringe drive over 1h at rt. IMes ·Cl =1,3-bis(mesityl)imidazoliumchloride; SIMes ·HCl =1,3-bis(mesityl)-4,5-dihydroimidazoliumchlor-ide; IPr ·HCl =1,3-bis(2,6-diisopropylphenyl)imidazoliumchloride; SIPr ·HCl =1,3-bis(2,6-diisopropyl-phenyl)-4,5-dihydroimidazoliumchloride. b Isolated yield not determined.

Ni(COD)2(0.06mmol), SIPr ·HCl (0.05mmol), and t -BuOK (0.05mmol) were stirred with 2mL of THF. Benzaldehyde (0.5mmol), phenylpropyne (0.5mmol), and silane were combined, diluted to a total volume of 2mL, and added to the reaction mixture via syringe drive over 1h at rt. b Concentration refers to the ﬁnal molarity of the aldehyde and alkyne starting components. c The catalyst was prepared in 38mL of THF.

improvements in regioselectivity compared with small ligand −small silane protocols were seen as silane concentration was lowered (Table2, entries 3−5). When 10equiv of (i -Pr) 3SiH was employed, regioselectivities began to approach the lower selectivities observed with Et 3SiH (Table2, entry 5). Even without altering silane stoichiometry, simply diluting the reaction mixture led to signi ﬁcant improvements in regiose-lectivity in reactions of (i -Pr) 3SiH with SIPr as ligand (Table2, entry 6). It should be noted that yields of protected allylic alcohol products were higher when the aldehyde, alkyne, and silane were all added by syringe drive to the catalyst mixture. Therefore, concentrations vary over the course of the reaction, but the impacts of stoichiometry and concentration were nonetheless essential variables as Table 2illustrates.

Next, to explore the impact of changing temperature, modi ﬁed outcomes can be judged against the observation that reactions using IMes with (i -Pr) 3SiH illustrated no impact of temperature on regioselectivity (Table3, entries 1and 2). Table 3. Temperature E ﬀects

Table 4. Reaction Scope with Optimized

Protocol

entry [**************]

R 1Ph

4-FC 6H 4n -Hept c -Hex Ph n -Hept Ph 2-furyl Ph c -Hex Ph Ph

R 2Ph Ph Ph Ph i -Bu i -Bu n -Pr n -Pr i -Pr i -Pr i -Pr n -Hex

R 3Me Me Me Me Et Et Et Me Me Me H H

method a

A A A A A A A A A A B B

5:6(%yield) >98:2(82)93:7(85)>98:2(77)>98:2(90)94:6(86)93:7(66)68:32(56)93:7(76)>98:2(78)>98:2(75)>98:2(61)95:5(69)

Method A:i -Pr 3SiH as reductant, reaction conducted at 0.125M in the aldehyde and alkyne at 50°C. Method B:t -Bu 2MeSiH as reductant, reaction conducted at 0.0125M in the aldehyde and alkyne with 22mol %Ni(COD)2at rt. b Conducted at 0.0125M in the aldehyde and alkyne.

entry 123456

NHC ligand IMes IMes SIPr SIPr SIPr SIPr

temp (°C)

rt 500rt 5095

5:6(%yield)

Ni(COD)2(0.06mmol), NHC •HCl (0.05mmol), and t -BuOK (0.05mmol), were stirred with 2mL of THF. Benzaldehyde (0.5mmol), phenylpropyne (0.5mmol), and silane (1.0mmol) were combined, diluted to a total volume of 2mL, and added to the reaction mixture via syringe drive over 1h. b Toluene was used as the reaction solvent.

However, by using the combination of (i -Pr) 3SiH with SIPr, a signi ﬁcant temperature e ﬀect was seen, with regioselectivities jumping from 68:32at 0°C up to 98:2at 95°C (Table3, entries 3−6). Whereas high temperatures provided the best regioselectivities, this comes at the expense of chemical yield, and more modest temperature increases in combination with the concentration e ﬀects noted above provide the best strategy for optimizing both yield and regioselectivity.

While previous e ﬀorts had shown some successes in regioselectivity reversals of aldehyde −alkyne reductive cou-plings, we sought to evaluate the above ﬁndings against a broader range of substrate combinations that led to modest regioselectivities or required noncommercial ligands in prior studies. To address this goal of a more general and convenient regioselective process, two optimized protocols were developed that could be applied to a wide range of alkynes. As shown in Tables 1−3, several di ﬀerent conditions could be used to access high regioselectivity with internal alkynes; however, heating the reaction to 50°C and using (i -Pr) 3SiH (methodA, Table 4) proved most e ﬃcient and versatile. With terminal alkynes, excellent regioselectivities upon heating came at the expense of chemical yield. Therefore, a second general procedure (methodB, Table 4) was developed for terminal alkynes using

commercially available (t -Bu) 2MeSiH and diluted reaction conditions while maintaining a room temperature protocol. Using optimized method A, phenyl propyne was coupled with a variety of aromatic and aliphatic aldehydes to produce regioisomer 5with high selectivity in all instances (Table4, entries 1−4). Steric in ﬂuences in the homopropargylic position were su ﬃcient to allow for excellent regiocontrol (Table4, entries 5and 6). However, when steric branching was decreased in the homopropargylic position (i.e.,comparing ethyl to n -propyl), a large erosion in regioselectivity was observed (Table4, entry 7). This very challenging case de ﬁnes the limits of the current strategy where very modest biases in alkyne substitution are present.

Not surprisingly, when the steric di ﬀerences were increased closer to the alkyne, excellent selectivity was maintained. For example, internal alkynes bearing a methyl substituent were well controlled as the aldehyde and large alkyne substituent were varied (Table4, entries 8−10). Terminal alkynes, which previously required the use of a noncommercial ligand to obtain regioisomer 5in high selectivity, could be coupled e ﬃciently using commercially available SIPr (Table4, entries 11and 12), although catalyst loading needed to be increased to achieve good chemical yields. It should be noted that for all of the illustrations in Table 4regioisomer 6would be expected using standard protocols, as has been previously reported for a number of the cases described.

Origin of Regioselectivity Reversals. As documented above, experimental conditions were identi ﬁed that provide a new handle for regioselectivity reversals across a broad range of substrates. The unique capabilities of this regioselectivity reversal strategy are well illustrated in couplings of aromatic alkynes. Phenyl propyne, for example, can now be converted to either regioisomer with very high selectivity as the above optimization studies illustrate (Tables1−3). The simplest explanation for the e ﬀects is that the rate-determining step for the standard protocol involves metallacycle formation (1to 2, Scheme 2a) leading to the preferred formation of 6, whereas

Scheme 2. Initial Mechanistic

Hypothesis

the rate-determining step for the new protocols using a large ligand, large silane, high temperature, and low concentration involves silane σ-bond metathesis (2to 3, Scheme 2b) leading to the preferred formation of 5. In related processes, the reversibility of metallacycle formation has been demonstrated, which would be required for the σ-bond metathesis step to be rate-determining. 9This hypothesis of changing rate-determin-ing step between the di ﬀerent experimental protocols suggested the evaluation of the experimental variations described above (Tables1−3).

Given that silane σ-bond metathesis had not been previously documented to be rate-determining in any of the prior experimental or computational studies of this reaction type, we sought to gain direct evidence for this mechanistic feature. Kinetic isotope e ﬀects using (i -Pr) 3SiH and (i -Pr) 3SiD in the above protocols were small and were little changed between protocols. 10However, initial rates experiments involving variations of silane concentration provide much more useful information in this context. 11

The dependence of initial rates on silane concentration was thus conducted with the experimental protocol described in this work following method A (Table4), except at an overall concentration of 0.0125M and without slow addition of any reagents. To our surprise, initial rates for the generation of products illustrated only a small rate dependence on the silane concentration. However, the origin of this e ﬀect became clear by analyzing the silane dependence in the generation of regioisomers 5and 6separately. As the plots of the rates of formation of the major product 5(Figure1a) and minor product 6(Figure1b) depict, the rate dependence varied sharply between the two product regioisomers. Upon varying silane concentration from 2.0to 6.0equiv at constant volume, the increase in rate of formation of the major regioisomer 5was very small, with a near-zero rate dependence. Alternatively, upon tracking the initial rates of the formation of the minor isomer 6, a signi ﬁcant rate dependence was noted with a near-Figure 1. (a)Initial rates for formation of 5. (b)Initial rates for formation of 6. (c)Ratio (6/5) of initial rates.

ﬁrst-order rate dependence. Plotting the ratios of initial rates of the product formation (initialrate of 6/initialrate of 5) across the range of silane concentrations provides a clear demon-stration of the changes in rate dependence for each regioisomer (Figure1c). Furthermore, the trend visible in this latter graph shows that regioselectivity should increase as silane concen-tration decreases, which explains the observation that syringe drive addition protocols and experiments at high dilution lead to exceptionally high regiocontrol.

The above initial rate data suggests, at least for the fast addition protocols, that the origin of the e ﬀects described above (Tables1−3) is that the rate-determining step is di ﬀerent for the two regioisomeric pathways (Scheme3). The formation of major regioisomer 5follows the previously observed mecha-nistic feature of rate-determining metallacycle formation (1a to 2a ), while the minor regioisomer 6follows a mechanism that involves rate-determining σ-bond metathesis (2b to 3b ). This di ﬀerence in behavior of 2a and 2b can be explained by the more crowded nickel center of 2b , due to the proximal position of the bulkier alkyne substituent (Phin this case). The concentration e ﬀects described above (Table2) can be rationalized by a mechanism involving di ﬀerent rate-determin-ing steps for the major and minor isomers (Scheme3), since only formation of product 6strongly depends on silane concentration. Similarly, the temperature e ﬀects (Table3) can

Scheme 3. Mechanism Invoking Di ﬀerent Rate-Determining Steps for Production of 5and

■

be rationalized, since the rate-determining step for the production of 5(i.e.,1a to 2a ) is a unimolecular rearrangement, whereas the rate-determining step for the production of 6(i.e.,2b to 3b ) is a bimolecular process involving two bulky components (metallacycle2b and (i -Pr) 3SiH), which thus proceeds with a large entropic penalty. The modi ﬁcation of reaction kinetics for only one of two regioisomeric products thus provides an unusual but e ﬀective handle for rational reversal of regioselectivity in a catalytic process.

While we are unaware of direct precedent for this regiocontrol strategy in reductive couplings, Ohmura and Suginome demonstrated a strategy with reversal of regiose-lectivity in alkyne silaborations by switching between reversible and irreversible alkyne insertion pathways using ligand control. 3a In other conceptually related advances, Waymouth demonstrated control in the reversibility of metallacycle formation as a strategy for controlling diastereoselectivity of zirconocene-catalyzed diene cyclomagnesiations. 12However, the simultaneous operation of di ﬀering kinetic descriptions for two regioisomeric pathways in a single reaction has not previously been described in reactions of this type.

While it is conceivable that a completely di ﬀerent mechanism involving direct oxidative additive of silane to Ni(0)could explain the silane rate dependence, several pieces of evidence argue against this. First, the increasing silane bulk required to introduce the silane rate dependence would disfavor silane oxidative addition on steric grounds. 13Second, the di ﬀering kinetic descriptions for formation of the two regioisomers, as documented in Figure 1, would not be expected by mechanisms involving silane oxidative addition to nickel. Third, silane oxidative addition pathways typically a ﬀord the products of aldehyde hydrosilylation 8,14a or alkyne hydrosilylation, 14b but not three-component coupling of the aldehyde, alkyne, and silane. The hydrosilylation of neither the aldehyde nor the alkyne proceeds e ﬃciently under the conditions (Table4, method A) where the three-component coupling e ﬃciently occurs. Finally, the aldehyde hydrosilylation processes proceed with a signi ﬁcant inverse kinetic isotope e ﬀect, 8which is not seen under the conditions developed in this study. For these reasons, the data reported herein are best interpreted as described as following the mechanism outlined in Scheme 3.

silane participates in the rate-and regiochemistry-determining step of the reaction for minor regioisomer production. This methodology possesses broad scope and improves the regioselectivity outcome for numerous substrate combinations by selecting for addition to the more hindered alkyne terminus.

ASSOCIATED CONTENT

Supporting Information *

Experimental details, kinetics analysis, and analytical data. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*[email protected]

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

We thank Dr. Hasnain Malik, Dr. Grant Sormunen, and Prof. Ryan Baxter for helpful suggestions and discussions. We are grateful to the National Institutes of Health (GM57014)for ﬁnancial support.

REFERENCES

(1)For processes involving nickel catalysis:(a)Montgomery, J. Organonickel Chemistry. In Organometallics in Synthesis ; Lipshutz, B. H., Ed.; John Wiley &Sons, Inc.:Hoboken, 2013; pp 319−428. (b)Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890. (c)Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem. Commun. 2007, 4441. (d)Tanaka, K.; Tajima, Y. Eur. J. Org. Chem. 2012, 3715.

(2)For processes involving other metals, see:(a)Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische, M. J. Angew. Chem., Int. Ed. 2014, 53, 9142. (b)Reichard, H. A.; McLaughlin, M.; Chen, M. Z.; Micalizio, G. C. Eur. J. Org. Chem. 2010, 391. (c)Bower, J. F.; Kim, I. S.; Patman, R. L.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34. (d)Huddleston, R. R.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 11488. (e)Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4664. (f)Barchuk, A.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 8432. (g)Liu, P.; Krische, M. J.; Houk, K. N. Chem. Eur. J. 2011, 17, 4021.

(3)For notable catalytic processes that demonstrate regiochemistry reversal:(a)Ohmura, T.; Oshima, K.; Taniguchi, H.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 12194. (b)Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961. (c)Jang, H.; Zhugralin, A. R.; Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 7859. (d)Park, J. K.; Ondrusek, B. A.; McQuade, D. T. Org. Lett. 2012, 14, 4790. (e)Han, L.-B.; Zhang, C.; Yazawa, H.; Shimada, S. J. Am. Chem. Soc. 2004, 126, 5080. (f)Wu, J. Y.; Moreau, B.; Ritter, T. J. Am. Chem. Soc. 2009, 131, 12915. (g)Tekavec, T. N.; Arif, A. M.; Louie, J. Tetrahedron 2004, 60, 7431. (h)Miller, Z. D.; Li, W.; Belderrain, T. R.; Montgomery, J. J. Am. Chem. Soc. 2013, 135, 15282. (i)Xu, K.; Thieme, N.; Breit, B. Angew. Chem., Int. Ed. 2014, 53, 2162. (j)Miller, Z. D.; Montgomery, J. Org, Lett. 2014, 16, 5486. (k)Ding, S. T.; Song, L. J.; Chung, L. W.; Zhang, X. H.; Sun, J. W.; Wu, Y. D. J. Am. Chem. Soc. 2013, 135, 13835.

(4)For early illustrations including those that involve regiocontrol through substrate bias, see:(a)Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, 4911. (b)Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098. (c)Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (d)Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (e)Malik, H. A.; Chaulagain, M. R.; Montgomery, J. Org. Lett. 2009, 11, 5734. (f)Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008, 10, 3829.

CONCLUSIONS

In summary, this study illustrates that a rational change in the regioselectivity-and rate-determining step of aldehyde −alkyne reductive couplings for one of the two possible regioisomers leads to a signi ﬁcantly improved regiocontrol strategy using commercially available ligands and silanes. The improvement in selectivity arises from a change in mechanism such that the

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(5)(a)Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342. Jamison, (b)T. Miller, F. J. Am. K. M.; Chem. Luanphaisarnnont, Soc. 2004, 126, T.; 4130. Molinaro, See also:C.; (c)127Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc. 20051181.

, 3694. (d)Bahadoor, A. B.; Micalizio, G. C. Org. Lett. 2006, 8, , Soc. (6)(a)2010Malik, , 132H. , 6304. A.; Sormunen, (b)Knapp-Reed, G. J.; Montgomery, B.; Mahandru, J. J. Am. G. Chem. M.; Montgomery, Houk, (7)(a)K. Liu, J. N. J. P.; J. Am. Am. McCarren, Chem. Soc. 2005, 127, 13156.

Chem. Soc. P.; 2010Cheong, , 132, 2050. P. H.-Y.; (b)McCarren, Jamison, T. P. R.; F.; Liu, Soc. Chem. 2009P.; Cheong, Soc. , 131P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. 2011, 6654. , 133, (c)6956. Liu, (d)P.; Haynes, Montgomery, M. T.; J.; Liu, Houk, P.; Baxter, K. N. J. R. Am. D.; Nett, 17495.

A. J.; Houk, K. N.; Montgomery, J. J. Am. Chem. Soc. 2014, 136, (8)Baxter, R. D.; Montgomery, J. J. Am. Chem. Soc. 2011, 133Chem. (9)(a)Soc. Ogoshi, 2006, S.; 128Tonomori, , 7077. (b)K.; Park, Oka, B. M.; Y.; Kurosawa, Montgomery, H. , J. 5728. T. Am. P.; Garza, (10)(a)V. J.; Primary Krische, kinetic M. J. isotope J. Am. Chem. e ﬀects Soc. of silane 2013, σ135-bond , 16320.

metathesis can well-de be very D. J. Am. ﬁned small, Chem. σ-bond for example, with the k H /k D as small as 1.15in some Soc. metathesis 2005, 127, processes. 643. (b)For See:an Sadow, outstanding A. D.; review Tilley, on T. the Hartwig, interpretation J. F. Angew. of kinetic Chem., isotope Int. Ed. effects, 2012see:, 51Simmons, , 3066. E. For M.; a comprehensive silanes, 111, 4857.

see:(c)overview Go m of KIE effects including those involving ez-Gallego, M.; Sierra, M. A. Chem. Rev. 2011, (11)Previous computational work 7c metathesis step (silaneaddition to the illustrated metallacycle) that proceeds the σ-bond by coordination interaction of silane to nickel, During these between processes, silicon followed by the development of an the and Si −H oxygen bond during length the is only transition very slightly state. elongated, state and cleavage of the Si −H bond occurs after the rate-determining energy maximum. step, For a this primary reason, kinetic even if isotope the silane the e ﬀects is involved transition-would be in expected step, the to concentration be small. If the of the silane silane is involved will in ﬂin uence the rate-determining the initial rates irrespective bond of the extent and timing of limitations metathesis. Si −H cleavage during the σ-of KIE For experiments.

this reason, evaluating initial rates avoids the Chem. (12)Knight, Soc. 1994K. , 116S.; , Wang, 1845.

D.; Waymouth, R. M.; Ziller, J. J. Am. (b)(13)2993. Ampt, (a)Corey, (c)Hester, K. A. M.; J. Y.; Braddock-Wilking, J. Chem. Rev. 1999, 99, 175. D. Duckett, M.; Sun, S. J.; B.; Harper, Perutz, A. R. W.; N. Dalton Yang, Trans. G. K. J. 2007Am. , Chem. Organometallics Soc. 19921987, 114, 6, , 632.

5234. (d)Hill, R. H.; Wrighton, M. S. Tetrahedron (14)(a)Lage, M. L.; Bader, S. J.; Sa-ei, K.; Montgomery, J. Montgomery, 2013J. Tetrahedron , 69, 5609. (b)2006Chaulagain, , 62, 7560.

M. R.; Mahandru, G. M.;

Regiocontrol in Catalytic Reductive Couplings through Alterations of Silane Rate Dependence

Evan P. Jackson and John Montgomery *

Department of Chemistry, University of Michigan, 930North University Avenue, Ann Arbor, Michigan 48109-1055, United States

Supporting Information *

provided. 7

Protocols

Received:November 16, 2014

allylic alcohol product. Both detailed kinetics studies and computational studies have provided evidence in support of this generalization. 7,8

RESULTS AND DISCUSSION

■

entry [1**********]11

ligand IMes IMes SIMes SIMes IPr IPr SIPr SIPr SIPr SIPr SIPr

R 3SiH Et 3SiH (i-Pr) 3SiH Et 3SiH (i-Pr) 3SiH Et 3SiH (i-Pr) 3SiH Et 3SiH

t -BuMe 2SiH t -BuPh 2SiH (i -Pr) 3SiH (t -Bu) 2MeSiH

5:6(%yield)

4:96b 4:96b 44:56b 56:44b 58:42(65)60:40(83)77:23(86)83:17(89)>98:2(61)

entry 123456

silane (equiv)Et 3SiH (2.0)Et 3SiH (10.0)(i-Pr) 3SiH (1.1)(i-Pr) 3SiH (2.0)(i-Pr) 3SiH (10.0)(i-Pr) 3SiH (2.0)

conc b (M)0.1250.1250.1250.1250.1250.0125c

5:6(%yield) 58:42(65)58:42(32)95:5(57)83:17(89)68:32(93)>98:2(82)

Table 4. Reaction Scope with Optimized

Protocol

entry [**************]

R 1Ph

4-FC 6H 4n -Hept c -Hex Ph n -Hept Ph 2-furyl Ph c -Hex Ph Ph

R 2Ph Ph Ph Ph i -Bu i -Bu n -Pr n -Pr i -Pr i -Pr i -Pr n -Hex

R 3Me Me Me Me Et Et Et Me Me Me H H

method a

A A A A A A A A A A B B

5:6(%yield) >98:2(82)93:7(85)>98:2(77)>98:2(90)94:6(86)93:7(66)68:32(56)93:7(76)>98:2(78)>98:2(75)>98:2(61)95:5(69)

entry 123456

NHC ligand IMes IMes SIPr SIPr SIPr SIPr

temp (°C)

rt 500rt 5095

5:6(%yield)

Scheme 2. Initial Mechanistic

Hypothesis

Scheme 3. Mechanism Invoking Di ﬀerent Rate-Determining Steps for Production of 5and

■

ASSOCIATED CONTENT

Supporting Information *

Experimental details, kinetics analysis, and analytical data. This material is available free of charge via the Internet at http://pubs.acs.org.

■■■

AUTHOR INFORMATION

Corresponding Author

*[email protected]

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

We thank Dr. Hasnain Malik, Dr. Grant Sormunen, and Prof. Ryan Baxter for helpful suggestions and discussions. We are grateful to the National Institutes of Health (GM57014)for ﬁnancial support.

REFERENCES

CONCLUSIONS

■

this reason, evaluating initial rates avoids the Chem. (12)Knight, Soc. 1994K. , 116S.; , Wang, 1845.

5234. (d)Hill, R. H.; Wrighton, M. S. Tetrahedron (14)(a)Lage, M. L.; Bader, S. J.; Sa-ei, K.; Montgomery, J. Montgomery, 2013J. Tetrahedron , 69, 5609. (b)2006Chaulagain, , 62, 7560.

M. R.; Mahandru, G. M.;

JACS-炔烃和醛的区域可调控的加成反应

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