B. Results and Discussion
2. Novel Insights into the Stereochemical Behaviour of Diastereomeric Cyclohexylzinc Reagents –
2.2. Results and Discussion
B. Results and Discussion 39 sec-butylzinc bromide using a chiral bisoxazoline-ligand.45 The resulting diastereomeric complexes displayed distinct proton signals for the methine group and could thus be probed for equilibration. An extremely slow inversion process was observed (t1/2= 4.0 months!).
Early experiments from our laboratories with stereodefined secondary alkylzinc reagents, however, suggested that the presence of salts considerably decreased the stability of the C-Zn bond by deteriorating the observed diastereoselectivities in quenching reactions with D2O.39b A DKR process and thus configurational lability were also hypothesized by Hayashi and Kumada for the enantioselective coupling of (1-phenylethyl)zinc halides with vinyl bromide using a chiral Pd-ferrocene catalyst.46
B. Results and Discussion 40 In preliminary experiments, we prepared the 2-substituted cyclohexylzinc reagents trans-(eq)-107 and 108 which are structurally identical but differ in stereochemical purity and subjected them to our Negishi-cross-coupling conditions (Scheme 31). While trans-(eq)-107 (trans:cis=
98:2) was stereoselectively prepared using hydroboration on 109 followed by a stereoretentive B-Zn exchange,39 108 was obtained as a mixture of diastereomers (trans:cis= 69:31) from LiCl-promoted Zn-insertion into the corresponding organic iodide 110.47,48 The stereochemical purity of these compounds was checked by deuterolysis with d-TFA (10 equiv.) at RT. All equatorially substituted trans-(eq)-107 was then subjected to Negishi-cross-couplings using Pd(dba)2 (2 mol%; dba: dibenzylideneacetone) and SPhos (2 mol%;
dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine)49 as catalyst system with several aryl iodides at RT. The respective arylated products 111a-b were obtained after 12-24 h in 90-93% yield (64-68% overall yield). Their diastereomeric purity (trans:cis= 98:2) completely reflected the stereochemical content of the starting organozinc trans-(eq)-107.
Thus, the cross-couplings had proceeded with complete retention of stereoconfiguration.
When the diastereomerically undefined 108 underwent the identical cross-coupling conditions with the same aryl iodides, 111a-b were obtained with 65-83% yield and diastereomeric ratios reaching from trans:cis 74:26 to 88:12. The diastereomeric purity had increased compared to the starting zinc reagent 108. In addition, however, the formation of regioisomers was observed (6-14%). Strikingly, when the cross-couplings were performed at lower temperatures (-25 °C to -10 °C), solely the all equatorially substituted, thermodynamically favourable trans-configured products were obtained (57-83% yield; trans:cis >99:1). The formation of regioisomers was thereby not observed. These results made us question our previous hypothesis of a DKR-driven stereoconvergence for two main reasons: 1) The configurationally defined, equatorially substituted trans-(eq)-107 reacted smoothly to give the products 111a-b with the same diastereomeric ratio, which does not corroborate the presumption of a fast equilibration between two thermodynamically almost equally favoured cyclohexylzinc diastereomers. 2) The observation of regioisomers in the cross-coupling reactions of stereochemically undefined 108 suggests that the axially substituted cis-(ax)-108 diastereomer may undergo distinct reaction pathways from trans-(eq)-108.
47 Krasovskiy, A., Malakhov, V., Gavryushin, A. & Knochel, P. Efficient synthesis of functionalized organozinc compounds by the direct insertion of zinc into organic iodides and bromides. Angew. Chem. Int. Ed. 45, 6040-6044 (2006).
48 Cohen, T., Gibney, H., Ivanov, R., Yeh, E. A.-H., Marek, I. & Curran, D. P. Intramolecular carbozincation of unactivated alkenes occurs through a zinc radical transfer mechanism. J. Am. Chem. Soc. 129, 15405-15409 (2007).
49 Barder, T. E., Walker, S. D., Martinelli, J. R. & Buchwald, S. L. Catalysts for Suzuki-Miyaura coupling processes: scope and studies of the effect of ligand structure J. Am. Chem. Soc. 127, 4685-4696 (2005).
B. Results and Discussion 41 In order to determine whether C-Zn bonds can invert on a relatively fast time scale (hours or minutes) and whether a fast equilibration was therefore possible, we decided to probe the configurational stability of trans-(eq)-d-112 and cis-(ax)-d-112 (Scheme 32).
Scheme 32: Test on the configurational stability of the C-Zn bond in substituted diastereomeric cis-(ax)-d-113 and trans-(eq)-d-113.
The remotely substituted cyclohexylzinc reagent d-112 (trans-(eq)-d-112 & cis-(ax)-d-112) which bears a tert-butyl-substituent in position 4 and a deuterium on carbon 1 geminal to the zinc enabled us to directly observe the stereochemical purity of the organozinc via 2H-NMR.
The bulky tert-butyl-group also functions as an anchor for the cyclohexyl ring ensuring that the diastereomeric zinc reagents differ only in the configuration of the C-Zn bond (axial (cis) vs. equatorial (trans)). Zn-insertion into the stereodefined 4-tert-butylcyclohexyl iodides cis-d-113 and trans-cis-d-113 resulted both in a cis:trans-mixture of d-112 (53:47). No change in the ratio was observed after 2 d at RT. EXSY-experiments showed no cross-signal for neither the deuterium in 2H- nor the deuterated carbon in 13C-NMR analysis over a period of 12 h. When the EXSY experiments were applied to 112, bearing a proton instead of the deuterium, cross-signals could be found for neither the methine proton nor carbon. A significant coalescence-shift was not observed in the 2H-NMR analysis of d-112 even upon heating to 50 °C.
Subjection of d-112 to quenching with TFA immediately and even after standing for 2 d at room temperature further confirmed the observed configurational stability of the cyclohexylzinc reagents.
It was now clear to us that due to the high configurational stability of the C-Zn bond a DKR mechanism which implies an equilibration between the diastereomeric zinc reagents and thus flipping of the C-Zn bond cannot be the cause of the observed stereoconvergence in the Negishi cross-coupling (Scheme 30). The mechanistic possibilities were now limited to either an equilibration on the stage of the Pd-intermediate (eq-104; Scheme 30), a Pd-salt induced equilibration or different stereochemical pathways for the diastereomeric cyclohexylzinc
B. Results and Discussion 42 reagents in which the equatorial C-Zn bond would react with retention and the axial C-Zn bond with inversion of stereoconfiguration in the transmetalation step selectively forming eq-104. Thus, aware of the pivotal influence of temperature on the diastereoselectivity in the Negishi-cross-coupling (Scheme 31), we decided to probe the stereochemistry of several diastereomeric cyclohexylzinc reagents in the deuterolysis with d-TFA and MeOD at different temperatures (Table 5).
Table 5: Deuterolysis of diastereomeric cyclohexylzinc reagents.
Entry Cyclohexylzinc Reagent D+/H+ -Source
Reaction Temp.
[°C]
Products d.r.
(eq:ax)a 1
108
d-TFA 25
trans-(eq)-114 + cis-(ax)-114
69:31
2 d-TFA -78 99:1
3 MeOD 25 99:1
4
115
d-TFA 25
trans-(eq)-116 + cis-(ax)-116
48:52
5 d-TFA -78 96:4
6 MeOD 25 87:13
7 MeOD 0 97:3
8
112
d-TFA 25
trans-(eq)-117 + cis-(ax)-117
67:33
9 d-TFA -78 >99:1
10 MeOD 25 >99:1
11
118
trans-(eq)-118 + cis-(ax1)-118 + cis-(ax2)-118
d-TFA 25
trans-(eq)-119 + cis-(ax)-119
66:34
12 d-TFA -78 76:24
13 MeOD 25 76:24
14 MeOD 0 90:10
15
120
d-TFA 25
cis-(eq)-121 + trans-(ax)-121
65:35
16 d-TFA -78 80:20
17 MeOD 25 76:24
18 MeOD 0 90:10
B. Results and Discussion 43
19
122
d-TFA 25
cis-(eq)-123 + trans-(ax)-123
58:42
20 d-TFA -78 79:21
21 MeOD 25 66:44
22 MeOD 0 84:16
23
124
d-TFA 25
men-(eq)-125 + neomen-(ax)-125
65:35
24 d-TFA -78 >99:1
25 MeOD 25 >99:1
26
126
d-TFA 25
ββββ-(eq)-127 + αααα-(ax)-127
82:18
27 d-TFA -78 >99:1
28 MeOD 25 >99:1
29
128
d-TFA 25
ββββ-(eq)-129 + αααα-(ax)-129
79:21
30 d-TFA -78 99:1
31 MeOD 25 90:10
32 MeOD 0 >99:1
33
d-126
TFA 25
αααα-(ax)-127 + ββββ-(eq)-127
88:12
34
d-112
TFA 25
cis-(ax)-117 + trans-(eq)-117
64:36
35 TFA -78 63:37
36 MeOH 25 87:13
37 MeOH 0 91:9
[a] Determined via 2H-NMR.
Thus, quenching of 108 with d-TFA, which had resulted in a cis:trans-ratio of 31:69 at RT, led almost exclusively to the trans-configured deuterated product trans-(eq)-114 (cis(ax):trans(eq)= 1:99) when performed at -78 °C (entries 1-2). Remarkably, replacing the strong acid d-TFA with the weak D+-source MeOD furnished trans-(eq)-114 (cis(ax):trans(eq)= 1:99) upon quenching at RT (entry 3). A similar behaviour was found for 115 bearing a less sterically demanding methyl-group in position 2 (entries 4-7). Interestingly, a cis(ax)/trans(eq)-ratio of deuterated product 116 of 13:87 was obtained when quenched with MeOD at RT (entry 6). This d.r. could be further improved to 3:97 when the reaction temperature was decreased to 0 °C (entry 7). For 112 bearing the tert-butyl anchor in position 4, the identical clear trend was observed: While quenching with d-TFA revealed the true
B. Results and Discussion 44 diastereomeric ratio of 112 (cis:trans= 33:67), exclusively trans-(eq)-117 was obtained when the reaction was performed at -78 °C (entries 8-9). Quenching with MeOD at RT gave trans-(eq)-117 with a diastereomeric purity of >99:1 (entry 10). Using 118 in which the tert-butyl anchor is replaced by a smaller methyl-group which allows the presence of an additional conformer for the axial cis-configured diastereomer cis-(ax2)-118 in which the methyl-group occupies an axial position while the C-Zn bond is oriented equatorially. Thus, the trend towards the all equatorially substituted, deuterated trans-product trans-(eq)-119 upon quenching at low temperature and with the weaker acid MeOD is less pronounced (entries 11-14). Upon quenching with MeOD at 0 °C a cis:trans-ratio of only 10:90 was achieved (entry 14). Almost identical ratios were obtained for the deuterolysis products cis-(eq)-121 and trans-(ax)-121 of the methyl-substituted cyclohexylzinc reagent 120 (entries 15-18). The 3-OTBS-substituted 122, in accordance with the lower a-value of oxygen-groups on cyclohexyl rings,50 displayed a smaller bias towards equatorial deuteration, as reflected by the ratio of cis-(eq)-123 and trans-(ax)-123 (entries 19-22). With MeOD-quenching at 0 °C, however, a trans(ax):cis(eq)-ratio of 84:16 was achieved (entry 19). The rigid menthyl- (124), cholesteryl- (126) and cholestanylzinc (128) reagents showed a very strong tendency towards equatorial deuteration with both d-TFA and MeOD (entries 23-32). Thus, for menthylzinc reagent 124, which gave a 65:35 mixture of men-(eq)-125 to neomen-(ax)-125 upon trapping with d-TFA at RT, only the menthyl-diastereomer men-(eq)-125 was obtained, when the temperature was decreased to -78 °C (entry 24). Also, quenching with MeOD at RT resulted only in the formation of men-(eq)-125 (entry 25). For rigid cholesteryl- (126) and cholestanylzinc iodide (128) quenching with d-TFA at RT resulted already in α(ax): β (eq)-ratios of 18:82 and 21:79 (entries 26 and 29). Quenching with d-TFA at -78 °C and MeOD resulted in a strong preference for the equatorially deuterated products ββββ-(eq)-127 and ββββ -(eq)-129 (entries 27-28, 30-32). In order to test whether these trends hold also true for protolysis, we performed analogous quenching reactions with the deuterated cyclohexylzinc iodides d-126 and d-112 using TFA and MeOH as proton sources (entries 33-37).51 Quenching d-126 with TFA at room temperature resulted already in a d.r. of 88:12 for the equatorially protonated product, thus corroborating the tendencies which were observed with the deuterolysis of 126 before (compare entries 26 and 33). The results for protolysis of d-112 were more remarkable: While trapping of d-112 with TFA at -78 °C and at RT both resulted in the same diastereomeric ratio (cis:trans= 36:64; 37:63; entries 34-35), quenching with
50 Eliel, E. L. Stereochemistry of carbon compounds (McGraw-Hill, New York, 1962).
51 Giagou, T. & Meyer, M. P. Kinetic isotope effects in asymmetric reactions. Chem. Eur. J. 16, 10616-10628 (2010).
B. Results and Discussion 45 MeOH, however, resulted in preferential equatorial protonation with cis:trans-ratios of 13:87 at RT and 9:91 at 0 °C (entries 36-37). This unequivocally proves the tendency of the axial C-Zn bond in the cis-configured diastereomer cis-(ax)-d-112 to undergo invertive quenching.
We also observed a dependence of the diastereoselectivity in the quenching reactions on the mode of addition (Scheme 33). While direct quenching of 112 with d-TFA at RT resulted in a cis:trans-ratio of 33:67, slow addition of d-TFA over 2 h gave almost exclusively trans-(eq)-117. (A test experiment showed that this result was a function of the time used for addition, not of the lower concentration of TFA.) The same trend was observed in the protolysis of d-112 with TFA.
Scheme 33: Comparison of direct and slow addition of d-TFA addition to 112.
Thereby, addition of TFA over 2 h led preferentially to cis-(ax)-d-112 (cis:trans= 89:11). The distinct chemical shifts of the deuterium atoms on d-112 (prepared without LiCl) and on the protonated products allowed us to follow the protolysis reaction of d-112 via 2H-NMR. Thus, TFA was added slowly via syringe pump and the d.r. of d-112 and the protonation product 117 was checked after several periods of time. Remarkably, the starting d.r. of d-112 (cis(ax-Zn):trans(eq-Zn)= 37:63) remained constant during addition of TFA. More strikingly even, the d.r. of the protonated compound did not alter considerably. Thus, when 5 mol% TFA were added after 2 min, already a cis(ax-H):trans(ax-H)-ratio of 83:17 was observed for 117. This ratio remained more or less the same after the addition of 20 mol% TFA after 20 min (85:15) and after 1 h, when quenching of d-112 was finished after 1 h upon a total 110 mol% TFA (87:13). Accompanying 2H-EXSY-NMR experiments showed no observable cross-peak, thus excluding an equilibration of the C-Zn bond on NMR timescale. These results along with the fact that only one Pd-intermediate could be observed in the cross-coupling show that the equatorial C-Zn bond must react with retention and the axial C-Zn bond with inversion of the stereoconfiguration in the transmetalation step to ArPdLnX thus leading to stereoconvergence
B. Results and Discussion 46 in the reaction. Therefore, we replace the DKR scenario with a mechanistic view in which the two diastereomeric cyclohexylzinc reagents react via distinct stereochemical (retentive vs.
invertive) pathways.
B. Results and Discussion 47