Stereoselective preparation of cyclopropylmagnesium reagents via a Br-Mg exchange using i-PrMgCl·LiCl in the presence of dioxane

Article abstract of DOI:10.1055/s-0028-1087487

The reaction of various cyclopropyl bromides with i-PrMgCl·LiCl in THF-dioxane provides the corresponding magnesiated cyclopropane reagents with complete retention of configuration. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087487

LETTER
67
Stereoselective Preparation of Cyclopropylmagnesium Reagents via a
Br–Mg Exchange Using i-PrMgCl⋅LiCl in the Presence of Dioxane
Stereoselective
P
h
r
Cyclopr
i
opylm
s
t
Reagen
i
ts an B. Rauhut, Christian Cervino, Arkady Krasovskiy, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5–13, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 30 September 2008
E+
i-PrMgCl⋅LiCl
Abstract: The reaction of various cyclopropyl bromides with
i-PrMgCl·LiCl in THF–dioxane provides the corresponding mag-
nesiated cyclopropane reagents with complete retention of configu-
ration.
THF–dioxane (10:1)
25 °C, 8 h
R
R
Br
Br
R
R
Mg⋅LiCl
Mg⋅LiCl
R
R
E
E
2
trans-1
cis-1
trans-3
cis-3
trans-2
E+
i-PrMgCl⋅LiCl
Key words: Grignard reactions, organometallic reagents, stereo-
selectivity, copper, carbocycles
THF–dioxane (10:1)
25 °C, 8 h
2
cis-2
Scheme 1 Stereoselective Br–Mg exchange using i-PrMgCl·LiCl in
THF–dioxane
Organomagnesium reagents are key organometallic inter-
mediates for organic synthesis.1,2 They can be used effi-
ciently for the functionalization of various cyclic
systems.3 Cyclopropanes are important ring systems dis-
playing numerous interesting properties.4 The stereose-
lective preparation of cyclopropyl organometallics is
therefore an important synthetic target.5 Whereas the stan-
dard preparation of these reagents is carried out through
the direct insertion of magnesium into an organic halide,6
this insertion into cyclopropyl halides is not stereo-
selective and provides an E/Z mixture of cyclopropyl-
magnesium reagents. Recently, we have reported that
i-PrMgCl·LiCl allows the performance of a Br–Mg ex-
change with numerous aromatic and heteroaromatic bro-
mides under exceedingly mild conditions.7 Moreover,
addition of 1,4-dioxane can additionally increase the rate
of the exchange reaction.8 Although the I–Mg exchange
on cyclopropanes is known,9 there is only one example for
the Br–Mg exchange on the corresponding bromocyclo-
propanes.10 Herein, we report a stereoselective synthesis
of organometallic cyclopropyl building blocks. Thus, sub-
stituted cyclopropyl bromides of type 1 can be smoothly
converted into the corresponding Grignard reagents 2
by using i-PrMgCl·LiCl in the presence of 1,4-dioxane or
s-Bu2Mg·LiCl.8 The subsequent reaction with various
electrophiles provides polyfunctionalized cyclopropanes
of type 3 with good yields and excellent stereoselectivity
(Scheme 1 and Table 1).
Although the exchange reaction of bromocyclopropane
1a with sec-Bu2Mg·LiCl proceeds in the same manner, we
have favored i-PrMgCl·LiCl which is commercially avail-
able.12 However, by using i-PrMgCl·LiCl without the ad-
dition of 1,4-dioxane, the exchange reaction was sluggish
and did not proceed to completion. The Cu(I)-mediated
acylation of 2a with benzoyl chloride furnished the cyclo-
propyl ketone 3b in 72% yield (entry 2). The cyclopropyl
thio derivative 3c was obtained in 68% yield after reaction
of 2a with tetramethylthiuram disulfide13 (25 °C, 2 h; en-
try 3 in Table 1). This opens new possibilities, since the
dimethyldithiocarbamate moiety can easily be converted
into various sulfur-containing products.13 The corre-
sponding cis isomer 2b was also obtained after eight hours
at 25 °C by the reaction of cis-(2-bromocyclopropyl)ben-
zene (1b) with i-PrMgCl·LiCl in THF–dioxane. Cu(I)-
catalyzed allylation and Cu(I)-mediated acylation led to
the desired difunctionalized cyclopropanes 3d and 3e in
78% and 72% yields, respectively, as single stereoisomers
(entries 4 and 5). A Br–Mg exchange reaction on 2-(trans-
4-fluorophenyl)bromocyclopropane (1c) proceeded under
the same conditions, and the resulting Grignard reagent 2c
displayed the same reactivity pattern as 2a (entries 6–8).
In all cases complete retention of configuration was ob-
served. Similarly, the 1,1- and 1,2-diphenyl-substituted
bromocyclopropanes 4 and 5 were converted into the
corresponding magnesiated derivatives by reaction with
i-PrMgCl·LiCl in THF–dioxane (Schemes 2 and 3).
Thus, the reaction of trans-(2-bromocyclopropyl)benzene
(1a) with i-PrMgCl·LiCl in a THF–dioxane (10:1) mix-
ture at 25 °C produced the Grignard reagent 2a within
eight hours of reaction time. After addition of allyl bro-
mide in the presence of CuCN·2LiCl11 (5 mol%) the de-
sired trans-disubstituted cyclopropane 3a was isolated in
74% yield as a single stereoisomer (entry 1 of Table 1).
Interestingly, for completion of the Br–Mg exchange re-
action with 1-bromo-2,2-diphenylcyclopropane (4) two
days at 25 °C were required, while trans-1,2-diphenyl de-
rivative 5 was more reactive and the reaction proceeded
cleanly in 16 hours at –16 °C (Schemes 2 and 3). In both
cases, the resulting Grignard reagents were reacted with a
standard set of electrophiles affording the desired trifunc-
tionalized cyclopropanes 6a–f and 7a–d in 62–91% yield.
Thus, the reaction with MeSO2SMe provided the thio-
SYNLETT 2009, No. 1, pp 0067–0070
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087487; Art ID: G32208ST
© Georg Thieme Verlag Stuttgart · New York

68
C. B. Rauhut et al.
LETTER
Table 1 Preparation and Reactions of Magnesiated Cyclopropanes of Type 2
Entry
1
Grignard reagent
Electrophile
Product of type 3
Yield (%)a
2a
3a
74b
72c
Br
Ph
2 Mg⋅LiCl
Ph
Ph
2
3
2a
2a
PhCOCl
3b
Ph
O
S
S
NMe2
S
3c
68
Me2N
S
Ph
2
4
5
2b
3d
78b
72c
Br
Ph
Mg⋅LiCl
Ph
2
Ph
2b
PhCOCl
DMF
3e
Ph
O
6
7
2c
3f
89
4-FC6H4
Mg⋅LiCl
4-FC6H4
CHO
2
2c
2c
3g
91b
Br
4-FC6H4
76c
Ph
8
PhCOCl
3h
4-FC6H4
O
a Yield of analytically pure products.
b Yield after transmetalation using CuCN·2LiCl (5 mol%).
c Yield after transmetalation using CuCN·2LiCl (1.1 equiv).
Br
E
1) i-PrMgCl⋅LiCl (2.0 equiv)
THF–dioxane (10:1), –16 °C, 14 h
2) E+ (2.2 equiv)
Ph
Ph
Ph
Ph
5
7a–d
7a: E = SMe: 72%
7b: E = CHO: 71%
7c: E = Allyl: 84%
7d: E = Ac: 75%
Scheme 3 Br–Mg exchange and subsequent reaction with various
electrophiles
Scheme 2 Br–Mg exchange and subsequent reaction with various
electrophiles
In summary, we have developed a stereoselective synthe-
sis of functionalized cyclopropylmagnesium compounds
starting from the corresponding cyclopropyl bromides us-
ing i-PrMgCl·LiCl in the presence of 1,4-dioxane.16,17 Ex-
tensions of this work to polyfunctionalized cyclopropanes
and their optically active analogues are currently under-
way in our laboratories.
methyl cyclopropanes 6a and 7a, while quenching with
DMF led to the cyclopropyl aldehydes 6b and 7b. Succes-
sive addition of CuCN·2LiCl (5 mol% to 1.1 equiv) al-
lowed us to perform an allylation with allyl bromide and
an acylation with an acid chloride affording cyclopro-
panes 6c,d and 7c,d (Schemes 2 and 3). Transmetalation
with zinc chloride (1.1 equiv, 1.0 M in THF) and Negishi
cross-couplings14 with an aryl iodide [Pd(dba)2 (2 mol%),
tfp (4 mol%)] and with an aryl bromide [Pd(OAc)2 (1
mol%), S-Phos (1.5 mol%)] led to the aromatic products
6e,f in 62–67% yield (Scheme 2).15
Acknowledgment
We thank the DFG, W. C. Heraeus GmbH (Hanau), Chemetall
GmbH (Frankfurt) and BASF AG (Ludwigshafen) for generous
gifts of chemicals.
Synlett 2009, No. 1, 67–70 © Thieme Stuttgart · New York

LETTER
Stereoselective Preparation of Cyclopropylmagnesium Reagents
69
fractions were dried (MgSO4) and after filtration the solvent
was removed in vacuo. Purification by flash
chromatography (pentane, silica gel) yielded 3a as a
colorless oil [117 mg, 74% or 3d (117 mg, 74%)].
References and Notes
(1) (a) Silverman, G. S.; Rakita, P. E. In Handbook of Grignard
Reagents; Marcel Dekker: New York, 1996. (b) Wakefield,
B. J. In Organomagnesium Methods in Organic Synthesis;
Academic Press: London, 1995. (c) Grignard Reagents:
New Developments; Richey, H. G. Jr., Ed.; Wiley: New
York, 1999.
(2) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.
Int. Ed. 2003, 42, 4302.
(3) (a) Lisko, J. R.; Jones, W. M. Organometallics 1985, 4, 944.
(b) Hackett, M.; Whitesides, G. M. J. Am. Chem. Soc. 1988,
110, 1449. (c) Wakamatsu, H.; Isono, N.; Mori, M. J. Org.
Chem. 1997, 62, 8917. (d) Trofimov, A.; Rubina, M.;
Rubin, M.; Gevorgyan, V. J. Org. Chem. 2007, 72, 8910.
(4) (a) de Meijere, A.; Wessjohann, L. Synlett 1990, 20.
(b) de Meijere, A.; Hopf, H. Chem. Rev. 2006, 106, 4785.
(c) Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107,
4493.
Spectroscopic data for 3a: 1H NMR (300 MHz, CDCl3): d =
7.09–7.32 (m, 5 H), 5.96 (ddt, J = 16.6, 10.2, 6.3 Hz, 1 H),
5.02–5.17 (m, 2 H), 2.18–2.23 (m, 2 H), 1.70–1.73 (m, 1 H),
1.12–1.23 (m, 1 H), 0.83–1.00 (m, 2 H). 13C NMR (75 MHz,
CDCl3): d = 144.0, 137.7, 128.6, 126.1, 125.7, 115.4, 38.4,
23.2, 22.8, 16.1. IR (film): 3066 (m), 3002 (m), 1640 (m),
1607 (m), 1497 (m), 1030 (w), 996 (w), 912 (s), 753 (m), 696
(vs) cm–1. MS (EI, 70 eV): m/z (%) = 158 (6), 118 (9), 117
(100), 116 (11), 115 (42), 104 (31), 103 (6), 91 (25), 78 (6),
77 (6). HRMS (EI, 70 eV): m/z calcd for C12H14: 158.1096;
found: 158.1082. Spectroscopic data for 3d: 1H NMR (300
MHz, CDCl3): d = 7.21–7.33 (m, 5 H), 5.80 (ddt, J = 16.5,
10.2, 6.3 Hz, 1 H), 4.91–5.03 (m, 2 H), 2.22 (ddd, J = 8.6,
8.6, 6.1 Hz, 1 H), 1.86–1.96 (m, 1 H), 1.69 (dddt, J = 15.5,
7.8, 6.4, 1.5 Hz, 1 H), 1.15–1.27 (m, 1 H), 1.01–1.09 (m,
1 H), 0.71–0.77 (m, 1 H). 13C NMR (75 MHz, CDCl3): d =
139.6, 138.4, 129.6, 128.2, 126.0, 114.7, 33.2, 21.4, 18.3,
9.7. IR (film): 3066 (m), 3002 (m), 2908 (w), 1640 (m), 1604
(w), 1498 (m), 1028 (w), 911 (s), 769 (m), 727 (w), 698 (vs)
cm–1. MS (EI, 70 eV): m/z (%) = 158 (3) [M+], 129 (11), 128
(10), 118 (10), 117 (100), 116 (11), 115 (41), 104 (37), 103
(9), 91 (24), 78 (8), 77 (8), 65 (5), 51 (5). HRMS (EI, 70 eV):
m/z calcd for C12H14: 158.1096; found: 158.1066.
(5) Abramovitch, A.; Fensterbank, L.; Malacria, M.; Marek, I.
Angew. Chem. Int. Ed. 2008, 47, 6865.
(6) (a) Rieke, R. D. Science 1989, 246, 1260. (b) Rieke, R. D.;
Hanson, M. V. Tetrahedron 1997, 53, 1925. (c) Lee, J.;
Velarde-Ortiz, R.; Guijarro, A.; Wurst, J. R.; Rieke, R. D.
J. Org. Chem. 2000, 65, 5428. (d) Piller, F. M.;
Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel, P.
Angew. Chem. Int. Ed. 2008, 47, 6802.
(17) Typical Procedure for the Preparation of 1-(2-Bromo-
cyclopropyl)-4-fluorobenzene (1c):15,18 A round-bottomed
flask equipped with a magnetic stirrer was charged with 1-
fluoro-4-vinylbenzene (6.11 g, 50.0 mmol), CHBr3 (50.5 g,
0.20 mol), pinacol (0.768 g, 6.50 mmol) and triethylbenzyl-
ammonium chloride (0.569 g, 2.50 mmol). NaOH (8.00 g,
0.20 mol in 8 mL H2O) was added dropwise and the reaction
mixture was stirred vigorously for 16 h. Then, the solids
were filtered off and washed with CH2Cl2 (50 mL). The
aqueous layer was extracted with CH2Cl2 (50 mL) and the
combined organic phases were dried (MgSO4). After
filtration the solvent was removed under reduced pressure
and the crude product was purified by distillation (100 °C,
2.5 mbar), furnishing 1-(2,2-dibromocyclopropyl)-4-
fluorobenzene as a colorless liquid (10.2 g, 70%). 1H NMR
(300 MHz, CDCl3): d = 1.98 (t, J = 8.0 Hz, 1 H), 2.16 (dd, J
= 10.5, 7.8 Hz, 1 H), 2.94 (dd, J = 10.2, 8.6 Hz, 1 H), 7.04–
7.11 (m, 2 H), 7.22–7.28 (m, 2 H). 13C NMR (75 MHz,
CDCl3): d = 27.9 (CH2), 28.5, 35.6 (CH), 115.7 (d, J = 21.6
Hz, CH), 130.9 (d, J = 8.2 Hz, CH), 132.2 (d, J = 3.1 Hz),
162.6 (d, J = 246.7 Hz, CF). IR (film): 1606 (m), 1510 (vs),
1434 (w), 1228 (s), 1220 (s), 1158 (m), 1102 (m), 1052 (m),
1038 (m), 1014 (w), 926 (w), 860 (m), 830 (vs), 818 (s), 730
(m), 676 (s), 634 (w) cm–1. MS (EI, 70 eV): m/z (%) = 215
(24), 213 (26), 135 (8), 134 (100), 133 (88), 107 (7), 67 (12),
57 (6). HRMS (EI, 70 eV): m/z calcd for C9H779Br2F:
291.8899; found: 291.8898.
(7) (a) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel,
F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V.-V. Angew.
Chem. Int. Ed. 2003, 42, 4302. (b) Krasovskiy, A.;
Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(c) Kopp, F.; Knochel, P. Org. Lett. 2007, 9, 1639.
(d) Kopp, F.; Wunderlich, S.; Knochel, P. Chem. Commun.
2007, 2075.
(8) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem. Int.
Ed. 2006, 45, 159.
(9) Vu, V. A.; Marek, I.; Polborn, K.; Knochel, P. Angew. Chem.
Int. Ed. 2002, 41, 351.
(10) Kopp, F.; Sklute, G.; Polborn, K.; Marek, I.; Knochel, P.
Org. Lett. 2005, 7, 3789.
(11) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2390.
(12) i-PrMgCl·LiCl is commercially available from Chemetall
GmbH (Frankfurt).
(13) Krasovskiy, A.; Gavryushin, A.; Knochel, P. Synlett 2005,
2691.
(14) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem.
Soc. 1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982,
15, 340. (c) Zeng, X.; Quian, M.; Hu, Q.; Negishi, E. Angew.
Chem. Int. Ed. 2004, 43, 2259.
(15) De Lang, R. J.; Brandsma, L. Synth. Commun. 1998, 28,
225.
(16) Typical Procedure for the Preparation of trans-(2-
Allylcyclopropyl)benzene (3a) and cis-(2-Allylcyclo-
propyl)benzene (3b): A dry and argon-flushed 10-mL flask,
equipped with a magnetic stirrer and a septum, was charged
with i-PrMgCl·LiCl (1.1 M in THF, 1.1 mmol, 1.1 equiv)
and 1,4-dioxane (0.1 mL). The cis- or trans-(2-bromocyclo-
propyl)benzene (1a or 1b, 197 mg, 1.0 mmol, 1.0 equiv) was
added neat at 25 °C. The resulting mixture was stirred at 25
°C for 8 h to complete the Br–Mg exchange (checked by
GC–MS analysis of reaction aliquots). Allyl bromide (145
mg, 1.2 mmol, 1.2 equiv) followed by CuCN·2LiCl (1.0 M
in THF, 0.01 mmol, 1.0 mol%) was added at 0 °C. The
mixture was warmed to 25 °C and was quenched with a sat.
aq NH4Cl solution (10 mL). The aqueous phase was
extracted with Et2O (3 × 20 mL). The combined organic
A dry and argon-flushed two-necked Schlenk flask,
equipped with a magnetic stirrer and a septum was charged
with LiBr (3.02 g, 34.8 mmol). The salt was dried (0.01
mbar, 5 h, 150 °C) and then dissolved in THF (30 mL) and
Et2O (30 mL). The solution was cooled to –80 °C and
n-BuLi (14.4 mL, 34.8 mmol, 2.42 M in hexane) was added,
and the reaction mixture was cooled to –110 °C. 1-(2,2-
Dibromocyclopropyl)-4-fluorobenzene (9.23 g, 31.6 mmol)
was added dropwise and the reaction mixture was stirred for
1 h at –100 °C. Then, ethanol (15 mL) was added and the
reaction mixture was warmed to 25 °C and was quenched
with a sat. aq NH4Cl solution (50 mL) and extracted with
EtOAc (3 × 50 mL). The combined organic layers were dried
Synlett 2009, No. 1, 67–70 © Thieme Stuttgart · New York

70
C. B. Rauhut et al.
LETTER
(MgSO4) and after filtration the solvent was removed under
reduced pressure. Flash chromatographic purification
(pentane, silica gel) furnished 1c a colorless liquid (3.37 g,
50%). 1H NMR (300 MHz, CDCl3): d = 1.37–1.55 (m, 2 H),
2.34–2.41 (m, 1 H), 2.94–2.99 (m, 1 H), 6.94–7.05 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 18.7 (CH2), 21.3 (CH), 26.2
(CH), 115.3 (d, J = 21.3 Hz, CH), 127.5 (d, J = 8.3 Hz, CH),
135.3 (d, J = 3.2 Hz), 161.5 (d, J = 244.3 Hz, CF). IR (film):
1608 (w), 1600 (w), 1510 (vs), 1444 (w), 1226 (vs), 1180
(w), 1160 (m), 1104 (m), 1070 (w), 1042 (w), 1014 (w), 982
(w), 934 (m), 890 (m), 860 (m), 818 (vs), 718 (m), 702 (m),
634 (w), 612 (s) cm–1. MS (EI, 70 eV): m/z (%) = 136 (8),
135 (100), 134 (7), 133 (26), 115 (13), 109 (14), 107 (4), 83
(4), 67 (2), 56 (3). HRMS (EI, 70 eV): m/z calcd for
C9H879BrF: 213.9793; found: 213.9777.
(18) Dehmlow, E. V.; Lissel, M.; Heider, J. Tetrahedron 1977,
33, 363.
Synlett 2009, No. 1, 67–70 © Thieme Stuttgart · New York

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