Reactivities of mixed organozinc and mixed organocopper reagents, 2. Selective n-alkyl transfer in tri-n-butylphosphine-catalyzed acylation of n-alkyl phenylzincs; an atom economic synthesis of n-alkyl aryl ketones

Article abstract of DOI:10.1016/j.tetlet.2009.01.082

Tri-n-butylphosphine-catalyzed acylation of mixed n-alkyl phenylzincs with aromatic acyl halides in THF is efficient in selective transfer of n-alkyl groups to produce n-alkyl aryl ketones in good yields. This route provides an atom economic organocatalyzed alternative to transition metal-catalyzed acylation of di-n-alkylzincs.

Full text of DOI:10.1016/j.tetlet.2009.01.082

Tetrahedron Letters 50 (2009) 1501–1503
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactivities of mixed organozinc and mixed organocopper reagents, 2. Selective
n-alkyl transfer in tri-n-butylphosphine-catalyzed acylation of n-alkyl
phenylzincs; an atom economic synthesis of n-alkyl aryl ketones
*
Ender Erdik , Özgen Ömür Pekel
Department of Chemistry, Ankara University, Science Faculty, Beßsevler, Ankara 06100, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Tri-n-butylphosphine-catalyzed acylation of mixed n-alkyl phenylzincs with aromatic acyl halides in THF
is efficient in selective transfer of n-alkyl groups to produce n-alkyl aryl ketones in good yields. This route
provides an atom economic organocatalyzed alternative to transition metal-catalyzed acylation of
di-n-alkylzincs.
Received 31 October 2008
Revised 26 December 2008
Accepted 15 January 2009
Available online 20 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Alkyl arylzincs
Mixed diorganozincs
Acylation
n-Alkyl aryl ketones
Tributylphosphine
Diorganozinc reagents(R2Zn) areimportantorganometalliccom-
pounds due to their high reactivity, ease of preparation and compat-
ibility with many functional groups.1 However, in their reactions,
only one of the R groups is transferred to the electrophile. Mixed
diorganozincs, R1R2Zn, in which one of the R groups has a lower rate
of transfer than the other have been developed.2 Ethyl and tert-butyl
groups were found to react more slowly than other alkyl, vinyl and
phenyl groups.2a–e Mixed diorganozincs, RRRTZn, which carry one
transferable group (RT) and one residual group (RR) have recently
proved to be synthetically useful.3 Knochel showed that trimethylsi-
lylmethyl (Me3SiCH2),3a neopentyl (t-BuCH2) and neophyl (PhMe2
CCH2) groups3b are excellent RR groups.
Our literature survey has revealed that the dependence of trans-
fer selectivity of the organyl groups in mixed diorganozincs, R1R2Zn,
on the reaction parameters has not been investigated in detail. In
continuation of our work on this subject, we recently reported that
the relative transfer ability of organyl groups in n-butyl phenylzinc
depends on the reaction conditions in their copper-catalyzed reac-
tion with benzoyl chloride in THF.4 We succeeded in controlling
n-butyl or phenyl group transfer by using N- or O-donor cosolvents
or an additive, such as tri-n-butylphosphine. In THF:N-methyl-2-
pyrrolidinone (NMP) (3:1) and in THF:diethyleneglycol dimethyl
ether (diglyme) (3:1), the n-butyl/phenyl group transfer ratio
was 9:1 whereas only n-butyl group transfer was observed in
THF:n-Bu3P. The n-butyl/phenyl group transfer/ratio was 1:9 in
THF: N,N,N’,N’-tetramethylethylenediamine (TMEDA) (2:1).
It is remarkable that the copper-catalyzed chemoselective acyl-
ation of mixed alkyl arylzincs with an acyl halide can be carried out
in THF:n-Bu3P or in THF:TMEDA to yield alkyl ketones or aryl ke-
tones in good yields, respectively.
In fact, acylation of organometallic compounds using acyl chlo-
rides, which are cheap acylating agents provides a direct and conve-
nient procedure for the synthesis of ketones5 and also overcomes
some typical drawbacks of Friedel–Crafts acylations such as reduced
functional group tolerance and limitations due to substituent-
directing effects. Diorganocuprates,6 transition metal-catalyzed
organolithiums,7 Grignard reagents8 and mono- and diorgano-
zincs1,9 are widely used organometallic species in acylation reac-
tions. Protocols for the synthesis of ketones by acylation of
Grignard reagents in the presence of a Lewis base (tri-n-butylphos-
phine10a ormorerecently, bis[2-(N,N-dimethylamino)ethyl]ether)10b
and acylation of diorganozincs in the presence of a Lewis acid
11
(AlCl3
) have also been reported. Mixed diorganocuprates,
RRRTCuM (M: Li, MgBr) with residual groups (RR = RO, RS, R2N, Me,
RC„C, PhSO2CH2) have been used for selective and effective transfer
of RT groups to acyl chlorides.6a However, there is no reported work
on selective acylation of mixed diorganozincs, RRRTZn. We therefore
decided to study the synthetic applicability of the acylation of n-al-
kyl arylzincs in more detail.
Herein, we report that acylation of n-alkyl phenylzincs with
aromatic acyl chlorides in the presence of tri-n-butylphosphine
* Corresponding author. Tel.: +90 312 212 67 20/1031; fax: +90 312 223 23 95.
E-mail address: erdik@science.ankara.edu.tr (E. Erdik).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.082

1502
E. Erdik, Ö. Ömür Pekel / Tetrahedron Letters 50 (2009) 1501–1503
provides an alternative atom economic route for the synthesis of n-
alkyl aryl ketones by acylation of di-n-alkylzincs in the presence of
transition metal catalysts.
made a brief examination of the acylation of alkyl phenylzincs 1
with acyl halides 2 in the presence of n-Bu3P 3. The results are
summarized in Table 1.
We first carried out copper-catalyzed acylation reactions of a
number of alkyl arylzincs with benzoyl chloride to determine the
transfer selectivity of alkyl or aryl groups in THF in the presence
of the cosolvents NMP, diglyme or TMEDA. We prepared alkyl aryl-
zincs by an in situ method, that is, arylzinc chloride, which was
prepared by transmetallation of arylmagnesium bromide, was al-
lowed to react with alkylmagnesium bromide. We determined
the relative transfer ability of the organyl groups by calculating
the GC yields of ketones using authentic samples in the acylation
of the following R1R2Zn reagents: (R1,R2@n-Bu, 4-MeC6H4; n-Bu,
4-MeOC6H4; n-heptyl, Ph). The n-alkyl/aryl group transfer ratios
were found to be about 8:1 in THF:NMP (3:1) and in THF: diglyme
(2:1), and 1:9 in THF:TMEDA (2:1), which are not that different
from those of n-BuPhZn. As observed, complete transfer of either
the R1 group or R2 group does not take place. We also acylated neo-
pentyl phenylzinc to check the transfer ability of a neopentyl group
since this group was reported as a residual group in a number of
reactions.3a–c However, neopentyl phenylzinc behaved similarly
to other n-alkyl phenylzinc reagents in the acylation with benzoyl
chloride under copper catalysis, that is, selective transfer of the
neopentyl group took place, in THF: diglyme (2:1).
Acylation of n-alkyl phenylzincs with benzoyl chloride occurs
chemoselectively to afford n-alkyl aryl ketones 4 in high yields (en-
tries 1–3). It was reported that n-alkyl carbanions produce excel-
lent yields whereas
a-branched carbanions provide lower yields
of ketones due to the formation of side products.10 Hence, we did
not examine the acylation of sec- and tert-alkyl phenylzincs, but
we did study the outcome of the benzoylation of hindered neopen-
tyl phenylzinc (entry 4). GC analysis using authentic samples of
neopentyl phenyl ketone and benzophenone showed that the neo-
pentyl group was not acylated chemoselectively, instead the phe-
nyl group was acylated in a low yield. However, GC–MS analysis
showed the formation of 5 as a co-product produced from the
Meerwein–Pondorf–Verley type reduction of benzoyl chloride with
neopentyl phenylzinc (Eq. 1).10
Thus, instead of further investigating the potential synthetic
transfer of organyl groups in alkyl arylzinc reagents in THF in the
presence of cosolvents, we carried out a detailed examination of
n-Bu3P catalysis for complete transfer of alkyl groups in alkyl aryl-
zincs to acyl halides. As reported in our recent paper,4 we found that
selective transfer of the n-butyl group in the benzoylation of n-butyl
phenylzinc could also be carried out in 86% yield in the presence of
n-Bu3P (1 equiv), but without CuI catalysis. We performed optimiza-
tion experiments on the amount of n-Bu3P required and the solvent.
We found that possible catalytic formation of benzoyl tri-n-butyl-
phosphonium chloride, (PhCO)P+(n-Bu)3Clꢀ,10a in the presence of
10% n-Bu3P also acylates the n-butyl group in n-butyl phenylzinc
in a yield of 83%. Carrying out the n-Bu3P-catalyzed benzoylation
in the presence of THF:NMP (3:1) or THF:diglyme (2:1), which
worked well for selective transfer of the n-butyl group did not
increase the yield.
ð1Þ
We also prepared a mixed 1,6-dizinc reagent by transmetallation of a
1,6-di-zinc reagent with 2 equiv of ZnCl2 and then by reaction of the
1,6-di-Grignard reagent with 2 equiv of phenylmagnesium bromide.
Acylation of PhZn(CH2)6ZnPh gave the expected 1,6-diketone,
PhCO(CH2)6COPh in good yield (entry 5). 4-Acetoxy-1-butyl phenyl-
zinc was also acylated successfully in a slightly lower yield (entry 6).
Acylation of n-butyl phenylzinc with 4-methylbenzoyl chloride
produced a high yield of the expected ketone (entry 7). However,
pivaloyl chloride did not acylate n-butyl phenylzinc chemoselec-
tively in the presence of 10 mol % of n-Bu3P. GC analysis using
authentic samples of n-butyl tert-butylketone10a and phenyl tert-
butylketone showed that both groups were acylated in low yields.
However, in the presence of 1 equiv of n-Bu3P, we were able to
acylate the n-butyl group chemoselectively but only in low yield
(entry 8). The use of succinoyl chloride for the acylation of n-butyl
phenylzinc did not give acylated products but polymeric by-prod-
ucts instead. However, succinoyl chloride was also reported to give
complex mixtures in the acylation of cuprates.12
Having confirmed that the acylation of n-butyl phenylzinc with
benzoyl chloride in THF in the presence of 10 mol % of n-Bu3P re-
sults in selective transfer of the n-butyl group in good yield, we
Table 1
n-Bu3P-catalyzed acylation of mixed n-alkyl phenylzincs in THFa
Entry
R1
R
Yieldb (%)
1
2
3
4
5
6
7
8
n-Bu
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
Me3C
77
80
n-heptyl
n-decyl
Np
PhZn(CH2)6
MeCOO(CH2)4
n-Bu
90
c
67d
54
e
83
n-Bu
38f
Compound 1 was prepared in situ by reacting PhZnCl with R1MgBr in THF. See
a
experimental, Ref. 13.
b
Isolated yield. The products were fully characterized by 1H NMR analysis.
Side product 5 formed. See text.
c
d
The product is the
a,x
-diketone: PhCO(CH2)6COPh.
e
Compound 1 (R1@MeCO(CH2)4) was prepared in situ by reacting R1ZnBr with
PhMgBr. See experimental, Ref. 13.
Scheme 1. A possible catalytic role for n-Bu3P in n-Bu3P-catalyzed acylation of
n-alkyl phenylzincs.
f
GC yield in the presence of 1 equiv of n-Bu3P.

E. Erdik, Ö. Ömür Pekel / Tetrahedron Letters 50 (2009) 1501–1503
1503
P. J. Org. Chem. 2002, 67, 79–85; (j) Soorukram, D.; Knochel, P. Org. Lett. 2004, 6,
2409–2411.
4. Erdik, E.; Ömür Pekel, Ö. J. Organomet. Chem. 2008, 693, 338–342.
5. Dieter, R. K. Tetrahedron 1999, 55, 4177–4236.
6. (a) Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
2001; (b) Organocopper Reagents. A Practical Approach; Taylor, R. J. K., Ed.;
Oxford University Press, 1994.
Depending on the formation of acyl n-butylphosphonium ions
as acylating reagents,10a we propose a possible sequence of reac-
tions that enables n-Bu3P to function in a catalytic mode for the
n-Bu3P-catalyzed chemoselective acylation of n-alkyl phenylzincs
to give n-alkyl ketones (Scheme 1).
In conclusion, we have shown that selective acylation of n-alkyl
groups in n-Bu3P-catalyzed reactions of mixed n-alkyl phenylzincs
reagents with aromatic acyl halides in THF is an efficient method
for the synthesis of n-alkyl arylketones.13 This route provides a sim-
ple and atom economic alternative to transition metal-catalyzed
acylation of di n-alkylzinc reagents. Further studies concerning the
functional group selectivity of mixed diorganozincs in acylation
and C–C and C–heteroatom coupling reactions are underway.
7. Wakefield, B. J. Organolithium Methods in Organic Synthesis; Academic: London,
1990.
8. (a) Wakefield, B. J. Organomagnesium Methods in Organic Synthesis; Academic:
London, 1995; (b)Handbook of Grignard Reagents; Silverman, G. S., Rakita, P. E.,
Eds.; Marcel Dekker: New York, 1996.
9. (a) Fillon, H.; Gosmini, C.; Perichon, J. Tetrahedron 2003, 41, 8199–8202; (b)
Karzmierski, I.; Bastienne, M.; Gosmini, C.; Paris, J. M.; Perichon, J. J. Org. Chem.
2004, 69, 936–942. and references cited therein; (c) Xu, H.; Ekoue-Rovi, K.;
Wolf, C. J. Org. Chem. 2008, 73, 7638–7650.
10. (a) Maeda, H.; Okamoto, J.; Ohmari, H. Tetrahedron Lett. 1996, 37, 5381–5384;
(b) Wang, X.-J.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurty, D.; Senanayake, C. H.
Org. Lett. 2005, 7, 5593–5595.
Acknowledgement
11. (a) Yang, C. X.; Patel, H. H.; Ku, Y. Y.; Shah, R.; Sawick, D. Synth. Commun. 1997,
27, 2125–2132; (b) Arisawa, M.; Torisawa, Y.; Kawahara, M.; Yamanaka, M.;
Nishida, A.; Nakagawa, M. J. Org. Chem. 1997, 62, 4237–4239.
12. Dieter, R. K.; Sharma, R. R.; Yu, H.; Gore, V. K. Tetrahedron 2003, 59, 1083–1094.
13. Typical procedure for the acylation of n-alkyl phenylzincs: All reactions were
carried out in oven-dried glassware under a positive pressure of nitrogen using
standard syringe-septum cap techniques. GC analyses were performed on a
Thermo Finnigan gas chromatograph equipped with a ZB-5 capillary column
packed with phenylpolysiloxane using the internal standard technique.14
Phenylzinc chloride was prepared by addition of 1 equiv of phenylmagnesium
bromide to a solution of 1 equiv of ZnCl2 in THF at ꢀ20 °C and stirring at that
temperature for 15 min. 4-Acetoxy-1-butylzinc chloride was prepared by
direct LiCl promoted insertion of Zn into 4-acetoxy-1-iodobutane.15 A two-
necked flame-dried flask was charged with ZnCl2 (10 mmol) in THF (10 ml) and
cooled to ꢀ20 °C. Phenylmagnesium bromide (10 mmol) was added at ꢀ20 °C
with stirring. To freshly prepared phenylzinc chloride, n-alkylmagnesium
bromide (10 mmol) was added and the mixture was stirred at that
temperature for 15 min. For the preparation of mixed 4-acetoxy-1-butyl
phenylzinc, 4-acetoxy-1-butylzinc chloride was mixed with phenylmagnesium
bromide. To the mixed n-alkyl phenylzinc and n-Bu3P (1 mmol, 0.2 ml), acyl
halide (10 mmol) was added dropwise and the reaction mixture was stirred at
room temperature for 1 h. The mixture was hydrolyzed by addition of 1M HCl
and subsequently extracted with Et2O. The combined ethereal solutions were
washed with aq NaHCO3 solution, dried, concentrated by rotary evaporation
and subjected to silica gel column chromatography with hexane:EtOAc (1:1) as
eluent to give n-alkyl aryl ketones. 1H NMR spectroscopic data of the acylation
products of selected reactions.
We thank Turkish Scientific and Technical Research Council,
Grant No. TBAG 106T644 for the financial support.
References and notes
1. (a) Erdik, E. Organozinc Reagents in Organic Synthesis; CRC: New York, 1996;
(b)Organozinc Reagents. A Practical Approach; Knochel, P., Jones, P., Eds.; Oxford
University: Oxford, 1999. Chapater 5; (c) Patai’s The Chemistry of Organozinc
Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, 2007;
(d)Functionalized Organometallics; Knochel, P., Ed.; Wiley-VCH: Weinheim,
2005.
2. (a) Laloe, E.; Srebnik, W. Tetrahedron Lett. 1994, 35, 5587–5591; (b) Johnson, J.
B.; Yu, P.; Fink, P.; Bercot, E. A.; Rovis, T. Org. Lett. 2006, 8, 4307–4310; (c) Wipf,
P.; Ribe, S. J. Org. Chem. 1998, 63, 6454–6455; (d) Oppolzer, W.; Radinov, R. N.
Helv. Chim. Acta 1992, 75, 170–173; (e) Lipshutz, B. H.; Randall, W. V.
Tetrahedron Lett. 1999, 40, 2871–2874; (f) Hupe, E.; Knochel, P. Org. Lett.
2001, 3, 127–130; (g) Bolm, C.; Herman, N.; Hildebrand, J. P.; Muniz, K. Angew.
Chem., Int. Ed. 2000, 29, 3465–3467; (h) Özçubukçu, S.; Schmidt, F.; Bolm, C.
Org. Lett. 2005, 7, 1407–1409; (i) Rudolph, J.; Bolm, C.; Norby, P. O. J. Am. Chem.
Soc. 2005, 127, 1548–1552; (j) Rudolph, J.; Rasmussen, T.; Bolm, C.; Norby, P. O.
Angew. Chem., Int. Ed. 2003, 42, 3002–3005; (k) Fontes, M.; Verdaguer, X.; Sola,
L.; Pericas, M. A.; Riera, A. J. Org. Chem. 2004, 69, 2532–2543; (l) Schinnerl, M.;
Seitz, M.; Kaiser, A.; Reiser, O. Org. Lett. 2001, 3, 4259–4262; (m) Kim, J. G.;
Walsh, P. H. Angew. Chem., Int. Ed. 2006, 45, 4175–4178; (n) Oppolzer, W.;
Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593–1594; (o) Srebnik, M.
Tetrahedron Lett. 1991, 32, 2449–2451; (p) Niwa, S.; Soai, K. J. J. Chem. Soc.,
Perkin Trans. 1 1990, 937–943.
3. (a) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.; Reddy, C. K. Angew.
Chem. Int. Ed. 1997, 36, 1496–1498; (b) Lutz, C.; Jones, P.; Knochel, P. Synthesis
1999, 312–316; (c) Lutz, C.; Knochel, P. J. Org. Chem. 1997, 62, 7895–7898; (d)
Trawerse, J. F.; Hoveyda, A. N.; Snapper, M. Org. Lett. 2003, 5, 3273–3275; (e)
Jones, P.; Knochel, P. J. Chem. Soc., Perkin Trans. 1 1997, 3117–3118; (f) Jones, P.;
Reddy, C. K.; Knochel, P. Tetrahedron 1998, 54, 1471–1490; (g) Reddy, C. K.;
Devasagayaray, A.; Knochel, P. Tetrahedron Lett. 1996, 37, 4495–4498; (h)
Rimkus, A.; Sewald, N. Org. Lett. 2002, 4, 3289–3291; (i) Jensen, A. E.; Knochel,
(Table 1, entry 2) 1H NMR (400 MHz ,CDCl3) d: 0.88 (t, 3H, J = 7.2 Hz), 1.26–1.36
(m, 8H), 1.74 (m, 2H), 2.95 (t, 2H, J = 7.2 Hz), 7.43–7.47 (m, 2H), 7.52–7.56 (m,
1H), 7.94–7.96 (m, 2H).
(Table 1, entry 5) 1H NMR (400 MHz, CDCl3) d: 1.43 (m, 4H), 1.75 (m, 4H), 2.97
(t, 4H, J = 7.2 Hz), 7.45 (m, 4H), 7.55 (m, 2H), 7.95 (dd, 4H, J = 7.6 Hz, J = 1.4 Hz).
(Table 1, entry 6) 1H NMR (400 MHz, CDCl3) d: 1.70–1.84 (m, 4H), 2.03 (s, 3H),
3.01 (t, 2H, J = 7.2 Hz), 4.01 (t, 2H, J = 7.2 Hz), 7.45 (m, 2H), 7.55 (m, 1H); 7.95
(m, 2H).
14. Leonard, J.; Lygo, B.; Procter, G. Advanced Practical Organic Chemistry; Blackie:
London, 1995.
15. Krocsovsky, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 6040–6044.