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1
Journal of Organometallic Chemistry xxx (2005) xxx–xxx
www.elsevier.com/locate/jorganchem
2 One-pot Pd-catalyzed hydrostannation/Stille reaction
3 with acid chlorides as the electrophiles
F
4 Kyoungsoo Lee, William P. Gallagher, Elli A. Toskey,
OO
5 Wenzheng Chong, Robert E. Maleczka Jr. *
6 Department of Chemistry, Michigan State University, 540 Chemistry, East Lansing, MI 48824, USA
7 Received 15 November 2005; accepted 16 November 2005
8
PR
9
10 Abstract
11 A one-pot hydrostannation/Stille coupling sequence amenable to the employment of acid chloride electrophiles has been developed.
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12 In this protocol, palladium mediated alkyne hydrostannations using Me3SnF/PMHS as an in situ trimethyltin hydride source are fol-
13 lowed by the addition of the acid chloride to afford a variety of a,b-unsaturated ketones in a single pot.
14 Ó 2005 Published by Elsevier B.V.
15
CT
16 Pd-catalyzed cross-couplings of organostannanes and one pot hydrostannation/Stille protocol to include acid 37
17 various electrophiles are convenient and widely used reac- chlorides among the viable electrophiles (Scheme 2). 38
18 tions for r-bond construction [1]. Despite the well-estab- As it were, the prospect of adopting a straightforward 39
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19 lished power of the Stille reaction, there are negative extension of our existing methodology with acid chlorides 40
20 issues associated with handling the often unstable and/or exposed a number of uncertainties. Unlike previously used 41
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21 toxic organostannanes used in these couplings [2]. To obvi- electrophiles, reactions with acid chlorides face a host of 42
22 ate direct manipulation of the stannane coupling partners, potential problems. For example, under our standard con- 43
23 our group has developed one-pot Pd-catalyzed hydrostan- ditions the triorganotin hydrides used in the hydrostanna- 44
24 nation/Stille coupling sequences [3] that begin with the tion step are prepared by the reduction of organotin halides 45
25 in situ generation of triorganotin hydrides [4]. The hydrides with polymethylhydrosiloxane (PMHS) in the presence of 46
CO
26 so formed react in situ with alkynes to form vinylstann- fluoride. Thus, we were confronted with the possibility of 47
27 anes, which without isolation undergo Stille cross-coupling residual tin hydride or PMHS reducing the acid chloride 48
28 reactions (Scheme 1). In earlier reports, we showed that [6] or the a,b-unsaturated ketone products [7]. In addition, 49
29 vinyl, aryl, and benzyl halides were all acceptable electro- while Stille reactions with acid chlorides have been done in 50
30 philes for this sequence [3]. Noticeably absent from this water [5b], we worried about acid chloride hydrolysis. Fur- 51
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31 group of electrophiles were acid chlorides. thermore, adventitious formation of HCl from the acid 52
32 We considered this omission problematic because acid chlorides could promote competitive protiodestannylation 53
33 chlorides represent an important class of Stille electrophiles of the vinyltin intermediates [8]. Lastly, decarbonylation 54
34 [5]. In StilleÕs earliest studies, he showed that reactions with [5a] of the palladium(II) oxidative addition intermediate 55
35 these compounds could efficiently produce a,b-unsaturated was also one of our concerns. Nonetheless, provided these 56
36 ketones [5a]. Thus, we sought to expand the scope of the problems could be defeated, achieving the synthesis of var- 57
ious a,b-unsaturated ketones from alkynes and acid chlo- 58
*
Corresponding author. Tel.: +1 517 355 9715x124; fax: +1 517 353
rides in a single pot using an organotin salt as the initial 59
1793. tin source, a single load of catalyst, and unpurified vinyltin 60
E-mail address: maleczka@chemistry.msu.edu (R.E. Maleczka Jr.). intermediates would be attractive. 61
0022-328X/$ - see front matter Ó 2005 Published by Elsevier B.V.
doi:10.1016/j.jorganchem.2005.11.041

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Bu3SnF, PHMS, Table 1
cat. TBAF, One-pot hydrostannation/Stille with acid chlorides using Bu3SnF
R H R
Ph 1.5 equiv Bu3SnF, O
1 mol% (Ph3P)2PdCl2;
1.6 equiv PMHS,
Ph, THF R' Cl
Br 1 mol % Pd2dba3,
R 4 mol % TFP, (1.3 equiv) O
Scheme 1.
cat. TBAF R' R
65 ˚C
THF, 2 h, rt
O Entry R Acid chloride Stille rxn Yielda
cat. Pd O
time (h) (%)
Bu3SnH R R' Cl
F
R Bu3Sn R' R 1 CH3 COCl 6 96
2 CH(CO2Me)2 6 84
OO
Bu3SnF
COCl
Scheme 2. 3 CH3 6 56
4 CH(CO2Me)2 F 3C 2 74 b
62 In starting our exploration of this putative one-pot 5 CH3 57
6
COCl
PR
63 sequence, we opted to use an ‘‘anhydrous’’ variation for S
64 the in situ generation of tributyltin hydride [4]. Thus,
CH3 6 63
65 Bu3SnF, PMHS, and a catalytic amount of TBAF were 6 COCl
O
66 reacted in the presence of an alkyne and an acid chloride.
67 Not surprisingly, this procedure gave little of the desired 7 CH3 1-Naphthoyl acid 10 31
68 a,b-unsaturated ketone as the acid chloride was consumed chloride
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69 by the Bu3SnF/PMHS/TBAF combination in advance of 8 CH3 COCl 10 91
70 the cross-coupling. To avoid this trouble, we simply added 9 CH(CO2Me)2 6 58
71 the acid chloride (without any additional Pd-catalyst) after a
Average isolated yield over two runs.
72 vinylstannane formation was complete (1 mol% Pd2dba3, b
The decarbonylated product was also observed.
73 4 mol% TFP, 1.5 equiv. Bu3SnF, 2.5 equiv. PMHS, cat.
CT
74 TBAF, THF, r.t., ca. 2 h or until complete by GC). Under
75 this two-step one-pot procedure a variety of a,b-unsatu-
76 rated ketones could be formed (Table 1).
77 This first generation study only employed alkynes that 1.5 equiv Bu3SnF,
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78 were tri-substituted at the propargylic position so that 2.5 equiv PMHS,
1 mol % Pd2dba3,
79 our evaluation of the process would not be complicated (71 %)
4 mol % TFP, cat. TBAF, Cl
RR
80 by the formation of regioisomers. The protocol proved THF, 2 h, rt; then +
81 workable with a variety of acid chlorides. Typically cross- CHO
82 couplings were achieved after 6–10 h at 65 °C and the 2-chlorobenzoyl chloride
(1.3 equiv), 65 oC, 6 h (32 %)
83 yields could be very high. However, in some cases intrusive Cl
84 amounts of side products were observed. For example,
CO
Scheme 3.
85 reactions with either 4-trifluoromethylbenzoyl chloride
86 (entry 4) or 2-chlorobenzoyl chloride (Scheme 3) witnessed
87 the formation of the corresponding benzaldehydes and the to 2 h [10]. More importantly; the observed increases in 103
88 decarbonylated coupling products [5a]. Moreover, despite reaction rates were generally met with substantially higher 104
89 our best efforts at reaction optimization some of the prod- yields and fewer visible side reactions. For example, the 105
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90 uct yields remained moderate at best. previously failed coupling of 2-chlorobenzoyl chloride 106
91 We attributed some of these problems to the relatively (entry 3) could now be achieved in an over all yield of 107
92 slow cross-coupling times. In our previously reported tin 86%. Other entries worthy of further comment include 108
93 catalyzed hydrostannation/Stille sequence with other sp2- the reaction of 4-bromobenzoyl chloride (entry 6). Despite 109
94 halides, switching from Bu3SnCl to the less sterically its two potential coupling sites (acid chloride and aryl bro- 110
95 demanding Me3SnCl gave faster reaction times and mide) this substrate chemoselectively reacted with the 111
96 decreased byproduct formation [9]. Looking for a similar in situ generated vinyl stannane at the acid chloride site 112
97 outcome for the two-step one-pot acid chloride coupling to afford the product in near quantitative yield [11]. Fur- 113
98 sequence, the initial tin species was changed from Bu3SnF thermore, that product did not suffer from any unwanted 114
99 to Me3SnF. In doing so, we were gratified to observe a sig- dehalogenation of the aryl bromide [12]. Likewise, cinna- 115
100 nificantly improved process. moyl chloride afforded the 1,4-diene-3-one in 81% yield 116
101 As illustrated in Table 2, using Me3SnF in place of without any 1,4-reduction [7] of this activated dienone 117
102 Bu3SnF typically decreased cross-coupling times from 6 (entry 12). 118

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Table 2
One-pot hydrostannation/Stille with acid chlorides using Me3SnF [10]
O
1.5 eq. Me3SnF, 2.5 eq. PMHS, (1.3 equiv) O
1 mol % Pd2dba3, 4 mol % TFP, R Cl
Me3Sn R
cat. TBAF, THF, 2 r, rt 65 ˚C
Entry Acid Stille Product Yielda Entry Acid chloride Stille Product Yielda
chloride rxn (%) rxn (%)
time (h) time (h)
O
F
COCl
1 2 94 7 2 99
COCl
OO
S S
O
O
MeO COCl MeO
2 2 96 8 COCl 2 95
MeO MeO O O
O
PR
OMe OMe
O
O
COCl
COCl
3 2 86 9 2 92
Cl Cl
ED
COCl O
4 2 72 10 COCl 2 90
NO 2 NO2 6 6
CT
O
NC COCl O
NC
COCl
5 2 98 11 4 92
E
O
O
COCl
COCl
RR
6 4 98 12 4 80
Br Br
a
Average isolated yield over two reactions.
CO
119 Unfortunately, even under these conditions not all sub- the Stille reaction time to 8 h to achieve the reported yield. 136
120 strates were universally accepted. As shown in entry 4, 4- In an attempt to circumvent the distal/proximal regiochem- 137
121 nitrobenzoyl chloride still gave the decarbonylated cou- ical matter, we first looked at performing the Pd-catalyzed 138
122 pling product, even when the reaction was run under an hydrostannation step on the 1-bromoalkyne derivative 139
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123 atmosphere of CO [5a]. [3b,8b]. However, for reasons that remain unclear, that 140
124 Finally, we examined a reaction sequence that started substrate did not work well in the hydrostannation/cross- 141
125 with an alkyne that was not fully substituted at the propar- coupling sequence. Another option involved running the 142
126 gylic position (Scheme 4). As previously mentioned such hydrostannation step under free radical conditions [4] 143
127 substrates afford measurable levels of the proximal vinylst- and then adding the acid chloride along with a Pd-catalysts 144
128 annanes under Pd-catalyzed conditions [4,8b,13]. Such to carry out the second step. Owing to the volatility [2] of 145
129 vinyltins are known to be sluggish Stille partners [1,14]. Me3SnH, we chose to run the radical hydrostannation with 146
130 This is reflected in the slightly diminished yield (71%) of Bu3SnH. While, this modified procedure was successful at 147
131 the cross-coupled product, which primarily arose from eliminating the proximal isomer (at the cost of some Z- 148
132 the selective cross-coupling of the distal vinyltin intermedi- vinylstannane formation), recourse to the tributyltin again 149
133 ate with the benzoyl chloride [15]. Furthermore, it must be gave the a,b-unsaturated ketone in only modest average 150
134 noted that for this substrate we were also required to add overall yield (42%). Usefully, the TBS ether survived the 151
135 an additional load of the palladium catalyst and extend fluoride present throughout both successful sequences. 152

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1.5 equiv Me3SnF, OTBS [2] (a) P.J. Smith (Ed.), Chemistry of Tin, Blackie Academic and 178
2.5 equiv PMHS, benzoyl chloride Professional, New York, 1998; 179
cat. TBAF, (1.3 equiv), (b) A.G. Davies (Ed.), Organotin Chemistry, VCH, New York, 1997. 180
[3] (a) W.P. Gallagher, R.E. Maleczka Jr., J. Org. Chem. 70 (2005) 841– 181
1 mol % (Ph3P)4Pd, Me3Sn (Ph3P)2PdCl2 846; 182
4 mol % TFP, 1 mol %, 183
+ proximal vinyltin (b) Also see: C.D.J. Boden, G. Pattenden, T. Ye, J. Chem. Soc.,
THF, 2 h, rt; then 65 oC, 8 h Perkin Trans. I (1996) 2417–2419. 184
(71%) [4] R.E. Maleczka Jr., L.R. Terrell, D.H. Clark, S.L. Whitehead, W.P. 185
Gallagher, I. Terstiege, J. Org. Chem. 64 (1999) 5958–5965. 186
OTBS OTBS [5] (a) J.W. Labadie, D. Tueting, J.K. Stille, J. Org. Chem. 48 (1983) 187
Ph 4634–4642; 188
(b) For selected recent examples, see: R. Lerebours, A. Camacho- 189
F
O Soto, C. Wolf, J. Org. Chem. 70 (2005) 8601–8604; 190
(c) T. Ichige, S. Kamimura, K. Mayumi, Y. Sakamoto, S. Terashita, 191
E. Ohteki, N. Kanoh, M. Nakata, Tetrahedron Lett. 46 (2005) 1263– 192
OO
benzoyl chloride 1267; 193
OTBS (1.3 equiv),
(Ph3P)2PdCl2
(d) K.R. Dieter, Tetrahedron 55 (1999) 4177–4236. 194
1.5 equiv Bu3SnF,
2.5 equiv PMHS, 1 mol % [6] J. Lipowitz, S.A. Bowman, J. Org. Chem. 38 (1973) 162–165. 195
[7] J.A. Muchnij, R.E. Maleczka, Jr. Chemoselective Conjugate reduc- 196
cat. AIBN Bu3Sn 65 ˚C, 3 h (42%) tion of a,b-unsaturated carbonyl compounds with poly- 197
toluene, 70 ˚C, 2 h + Z-vinyltin methylhydrosiloxane. In: Proceedings of the 37th Organosilicon 198
PR
Symposium, Philadelphia, PA, 2004; Poster P-34. 199
Scheme 4. [8] (a) S.A. Hitchcock, D.R. Mayhugh, G.S. Gregory, Tetrahedron Lett. 200
36 (1995) 9085–9088; 201
´
(b) H.X. Zhang, F. Guibe, G. Balavoine, J. Org. Chem. 15 (1990) 202
153 In summary, we have expanded the one-pot hydrostan- 1857–1867. 203
154 nation/Stille coupling method to allow acid chlorides to [9] R.E. Maleczka Jr., W.P. Gallagher, I. Terstiege, J. Am. Chem. Soc. 204
122 (2000) 384–385. 205
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155 serve as the electrophilic coupling partner. Problems asso-
[10] Typical reaction procedure: Pd2dba3 (0.01 mmol, 9.2 mg) and TFP 206
156 ciated with the use of these reactive building blocks can be (0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting 207
157 avoided by adding the acid chloride to the reaction after mixture was stirred at r.t. for 15 min. At that time, 3,3-dimethyl 1- 208
158 the vinylstannane has been produced in situ from butyne (1 mmol, 0.125 mL), Me3SnF (1.5 mmol, 274 mg), PMHS 209
159 Me3SnF/PMHS generated Me3SnH and a corresponding (2.5 mmol, 0.09 mL), and TBAF (1 drop of a 1 M solution in THF 210
CT
160 alkyne. Both aliphatic and electronically varied aromatic (0.008 mmol)) were added successively. The reaction was then 211
allowed to stirr at r.t. for 2 h, at which time the hydrostannation was 212
161 acid chlorides can be employed in this one-pot synthesis complete by GC. The acid chloride (1.3 mmol) was then added and 213
162 of a,b-unsaturated ketones. the mixture was allowed to stirr at reflux (65 °C) until the cross- 214
coupling was judged complete by TLC (2–4 h). At that time, the 215
reaction was diluted with saturated aq. KF (3 mL) and stirred for 0.5 216
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163 Acknowledgments
h. The reaction was extracted with Et2O and H2O and the aqueous 217
phase was back extracted with Et2O. The combined organics were 218
164 We thank the NIH (HL-58114), NSF (CHE-9984644),
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dried over MgSO4, filtered, and concentrated. The resulting residue 219
165 and the Yamanouchi USA Foundation for generous sup- was purified by silica gel chromatography to afford the corresponding 220
166 port. E.A.T. thanks the NSF REU Program (NSF a,b-unsaturated ketone. 221
167 0138932) at MSU for the opportunity granted. [11] Such chemoselectivity has been previously observed. See: Ref. [5b]. 222
[12] R.E. Maleczka Jr., R.J. Rahaim, R.R. Teixeira, Tetrahedron Lett. 43 223
(2002) 7087–7090. 224
CO
168 Appendix A. Supplementary data [13] (a) N.D. Smith, J. Mancuso, M. Lautens, Chem. Rev. 100 (2000) 225
3257–3282; 226
169 Supplementary data associated with this article can be (b) M.B. Rice, S.L. Whitehead, C.M. Horvath, J.A. Muchnij, R.E. 227
170 found, in the online version, at doi:10.1016/j.jorganchem. Maleczka Jr., Synthesis (2001) 1495–1504, and references cited; 228
171 2005.11.041. (c) K. Kikukawa, H. Umekawa, F. Wada, T. Matsuda, Chem. Lett. 229
(1988) 881–884; 230
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´
(d) H.X. Zhang, F. Guibe, G. Balavoine, Tetrahedron Lett. 29 (1988) 231
172 References 619–622; 232
(e) Y. Ichinose, H. Oda, K. Oshima, K. Utimoto, Bull. Chem. Soc. 233
173 [1] (a) J.K. Stille, Pure Appl. Chem. 57 (1985) 1771–1780; Jpn. 60 (1987) 3468–3470. 234
174 (b) J.K. Stille, B.L. Groh, J. Am. Chem. Soc. 109 (1987) 813–817; [14] X. Han, B.M. Stoltz, E.J. Corey, J. Am. Chem. Soc. 121 (1999) 7600– 235
175 (c) J.K. Stille, Angew. Chem., Int. Ed. Engl. 25 (1986) 508–523; 7605. 236
176 (d) V. Farina, V. Krishnamurthy, W.J. Scott, Org. React. 50 (1997) [15] The cross-coupling of 4-methoxybenzoyl chloride afforded the corre- 237
177 1–652. sponding a,b-unsaturated ketone in only 33% yield. 238
239