SN2′ Alkylation of cyclopropanols via homoenolates

Article abstract of DOI:10.1002/anie.201205190

Reining in reactivity: Stereoselective S_N2′ alkylation of cyclopropanols has been devised under the control of mixed zinc/copper reagents. This method provides convenient access to enantiopure keto homoenolates which react with electrophiles (E

Full text of DOI:10.1002/anie.201205190

Angewandte
Chemie
DOI: 10.1002/anie.201205190
Synthetic Methods
SN2’ Alkylation of Cyclopropanols via Homoenolates**
Pragna Pratic Das, Ken Belmore, and Jin Kun Cha*
Metal homoenolates are characterized by the juxtaposition of
an organometallic species b to a carbonyl group. These
bifunctional reagents require a delicate balance between
ꢀ
stability and reactivity for applications in C C bond forma-
tions. A particularly useful class of homoenolates is zinc
homoenolates. It is not surprising that known zinc and related
metal homoenolates are limited primarily to those bearing
weakly electrophilic esters, amides, and nitriles.[1,2] In con-
trast, little is known about zinc homoenolates of ketones and
aldehydes because of the known proclivity of metal homo-
enolates to cyclize into the corresponding cyclopropoxides.[3]
An attractive synthesis of cyclopropanols by treatment of a,b-
epoxy ketones with CH2(ZnI)2 indeed corroborates facile
cyclization of zinc keto homoenolates to the corresponding
cyclopropoxides.[4] Nonetheless, we hypothesized that subse-
quent transmetalation with a suitable metal could shift the
otherwise unfavorable equilibrium to generate b-keto homo-
enolates for subsequent elaboration [Eq. (1); M = metal]. As
Scheme 1. A working hypothesis on the generation of b-keto homoeno-
lates.
cooled to ꢀ308C. The reaction mixture was slowly warmed to
room temperature to afford the allylation product 3a in 84%
yield (entry 1).[11,12] GC/MS analysis of the crude reaction
mixture indicated the absence of the allylation product arising
from the ethyl-group transfer. A cursory survey of other metal
alkoxides revealed that a zinc alkoxide is particularly
effective, probably because of its softness compared to
other metals (e.g., Na+, Li+, Mg+2, and Ti+4).
part of research programs on synthetic applications of the
Kulinkovich cyclopropanation,[5,6] we report herein the prep-
aration and in situ SN2’ alkylation of mixed zinc/copper keto
homoenolates.
Treatment of cyclopropanol with diethylzinc should result
in formation of the zinc alkoxide A and ethane (Scheme 1). A
could be in equilibrium with the homoenolate B, where the
former is expected to be strongly favored. In situ trapping of
B by transmetalation could afford D for subsequent reactions.
Depending on the nature of the metal, an alternate sequence
of transmetalation/ring opening (A!C!D) cannot be ruled
out.[7] Among extensive prior art in the reactions of mixed
zinc/copper reagents, as well as organocopper chemistry,[8,9]
We next examined the allylation reactions of (ꢁ)-1 with
other allylating reagents under identical reaction conditions
to determine regioselectivity (SN2 versus SN2’). A broad range
of allylic halides gave the products 3a–h in good yields
(Table 1, entries 1–8). Most importantly, exclusive formation
of the SN2’ products was clearly seen from the results in
entries 5–8, independent of the substitution pattern (with no
deleterious influence by substituents at the 3-position). Thus,
the products involving formation of a quaternary center were
obtained in comparable yields (entries 7 and 8). These
remarkably selective SN2’ reactions are noteworthy, especially
because zinc homoenolates of esters were reported to require
polar additives (such as HMPA or DMF) for high levels of
SN2’ selectivity, as well as good yields.[1b] Both terminal and
internal propargylic halides or sulfonates displayed the
identical regiochemical outcome to yield the corresponding
allenes (entries 9–12). Different cyclohexenyl derivatives
were evaluated to assess nucleofugality and the following
trend was found in both rates and yields: bromide 2m >
phosphate 2n > pentafluorobenzoate 2o (entries 13–15).
A survey of the literature disclosed two closely related
ꢀ
we chose to asses allylation in this C C bond-forming
reaction.[10]
Upon addition of diethylzinc to a THF solution of the
(racemic) cyclopropanol (ꢁ)-1, vigorous gas evolution was
observed (Table 1). CuCN·2LiCl and allyl bromide (2a) were
then added successively to the mixture, which had been
[*] Dr. P. P. Das, Prof. Dr. J. K. Cha
precedents by the groups of Knochel[10a,d] and Matsubara[4c]
:
Department of Chemistry, Wayne State University
5101 Cass Ave, Detroit, MI 48202 (USA)
E-mail: jcha@chem.wayne.edu
regiochemistry was not addressed, except for only two
examples; surprisingly, the opposite SN2 regioselectivity was
reported with geranyl bromide (2h)[10a] and prenyl chloride
(2g’),[4c] which contrasts this work (Table 1, entries 5–8). The
origin for the striking reversal in regioselectivity between the
two procedures is unclear and must await further studies.
Alkylation of cis- and trans-1,2-dialkyl-substituted cyclo-
propanols with the allyl bromides 2a and 2g was carried out
Dr. K. Belmore
Department of Chemistry, The University of Alabama
Tuscaloosa, AL 35487 (USA)
[**] We thank the NSF (CHE-1212879) for generous financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205190.
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Table 1: SN2’ Alkylation of Cyclopropanol (ꢁ)-1.
Table 2: Additional examples with 2a and 2g.[a,b]
Entry
Cyclopropanol
Product
Yield [%][c]
1
2
4a: R1 =OBn
5a: R1 =OBn
92
63
Entry
1
El-LG[a]
Product
Yield [%][b]
84
4b: R1 =N(Boc)Ts
5b: R1 =N(Boc)Ts
=
El: CH2CH CH2
2a
3a
3[d]
82
=
El: CH2C(Br) CH2
2
3
4
74
85
87
6
7
2b
2c
3b
=
El: CH2C(Me) CH2
30,[a] 82[d]
72
3c
4
5
8a: R2 =H
9a: R2 =H
8b: R2 =OTBS
9b: R2 =OTBS
=
El: CH2C(CO2Et) CH2
2d
2e
2 f
3d
=
El: CH(Me)CH CH2
6
49
5
6
84[c]
80[c]
3e
=
El: CH(Ph)CH CH2
10
11
3 f
=
El: CMe2CH CH2
7[b]
73
93
7
2g
80
78
3g
2g’
12
14
13
15
8
76[c]
8[e]
2h
2i
3h
= =
El: CH C CH2
9
82
3i
[a] Reaction conditions: Et2Zn (1.0 equiv), CuCN·2LiCl (1.5 equiv), 2a or
2g (1.5 equiv). [b] Reaction conditions: THF, ꢀ308C to RT. [c] Yields are
those of the isolated product. [d] Used 2.0 equiv of Et2Zn. [e] A 2:1
diastereomeric mixture of 14 was used and yielded 15 in an identical
ratio of diastereomers. Bn=benzyl, Boc=tert-butoxycarbonyl, Piv=pi-
valoyl, TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl, Ts=4-tolu-
enesulfonyl.
= =
El: C(TMS) C CH2
10
81
2j
3j
= =
El: CMe C CH2
11
12
85
79
2k
3k
= =
El: CnBu C CHiPr
2l
3l
by employing nonracemic compounds,[13] as exemplified by
the results in entries 5–9, wherein the allylation products were
obtained as single diastereomers. Also included was the
preparation of attractively functionalized allenes 29 and 30
(entries 8 and 9).
13
14
15
2m
2n
2o
90[c]
60[c]
55[c]
3m
A characteristic preference for SN2’ over SN2 regioselec-
tivity is apparent in exclusive formation of 19, 21, 23, and 27
(Table 3). The stereochemical configuration of 23 was deter-
mined by one- and two-dimensional NMR experiments to
reveal the exclusive axial attack by 22 at 18 (entry 4).
Diastereofacial selectivity was anticipated to be anti by
analogy to ample literature precedents on the SN2’ reactions
of mixed zinc/copper reagents.[8,10,14] The dihydropyrans 32
and 33 were obtained as additional examples, and their
stereochemical assignment was made by comparison with 34a
(Scheme 2).[15] Notably, the phosphates 35 and 36, which are
epimeric to 31 and 16, respectively, were recovered unreacted.
In conclusion, we have developed a stereoselective
method for SN2’ alkylation of cyclopropanols via mixed zinc/
copper homoenolates of ketones. Cyclopropanols can be
viewed as a new class of enantiopure and attractively
functionalized b-keto alkylzinc reagents. Mechanistic studies
are currently in progress.
[a] LG = Leaving group. [b] Yields are those of isolated products.
[c] Diastereomeric ratio: 1:1. THF=tetrahydrofuran, TMS=trimethyl-
silyl.
under identical reaction conditions to establish the scope and
limitations of the method (Table 2). A wide range of cyclo-
propanols bearing common functional groups underwent
allylation in moderate to good yields, and clean SN2’
regioselectivity was again confirmed for 12!13 (entry 7).
With cyclopropanols containing a free hydroxy group (e.g., 6
and 8a), an extra equivalent of Et2Zn was necessary to obtain
higher yields (entries 3 and 4). The a-hydroxyketone 9a was
thus isolated in 82% yield, free from tautomerization, which
is indicative of mild reaction conditions. Additional examples
involved the use of nonracemic allylating reagents (Table 3).
A rapid increase in molecular complexity was made possible
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Table 3: Additional examples with nonracemic El+.[a]
Entry
Cyclo-
El-LG
Product
Yield [%][b]
propanol
1
(ꢁ)-1
70
16
18
17
2
3
(ꢁ)-1
(ꢁ)-1
74
62
19
21
20
18
4
5
6
7
58
62
65
65
22
12
23
24
26
27
16
16
Scheme 2. Additional examples.
25
12
[2] M. T. Crimmins, P. G. Nantermet, Org. Prep. Proced. Int. 1993,
25, 41.
(1R)-myrtenyl
bromide
[3] Previous examples were limited to mercury, tin, silver, and
copper species: a) I. Ryu, K. Matsumoto, M. Ando, S. Murai, N.
Sonoda, Tetrahedron Lett. 1980, 21, 4283; b) I. Ryu, M. Ando, A.
Ogawa, S. Murai, N. Sonoda, J. Am. Chem. Soc. 1983, 105, 7192;
c) I. Ryu, S. Murai, N. Sonoda, J. Org. Chem. 1986, 51, 2389.
[4] a) K. Nomura, K. Oshima, S. Matsubara, Angew. Chem. 2005,
117, 6010; Angew. Chem. Int. Ed. 2005, 44, 5860; b) K. Nomura,
S. Matsubara, Chem. Lett. 2007, 36, 164; c) K. Nomura, S.
Matsubara, Chem. Asian J. 2010, 5, 147; d) K. Nomura, S.
Matsubara, Chem. Eur. J. 2010, 16, 703; See also: e) K. Cheng,
P. J. Carroll, P. J. Walsh, Org. Lett. 2011, 13, 2346.
[5] For reviews, see: a) O. G. Kulinkovich, A. de Meijere, Chem.
Rev. 2000, 100, 2789; b) O. G. Kulinkovich, Chem. Rev. 2003, 103,
2597; c) O. G. Kulinkovich, Russ. Chem. Bull. Int. Ed. 2004, 53,
1065; d) A. Wolan, Y. Six, Tetrahedron 2010, 66, 15.
[6] a) O. L. Epstein, S. Lee, J. K. Cha, Angew. Chem. 2006, 118,
5110; Angew. Chem. Int. Ed. 2006, 45, 4988; b) H. G. Lee, I.
Lysenko, J. K. Cha, Angew. Chem. 2007, 119, 3390; Angew.
Chem. Int. Ed. 2007, 46, 3326.
8
9
12
25
60
70
28
28
29
30
[a] Reaction conditions: Et2Zn (1.0 equiv), CuCN·2LiCl (1.5 equiv), El+
(1.5 equiv), THF, ꢀ308C to RT. [b] Yields are those of the isolated
product. Ms=methanesulfonyl.
[7] Depending on metals, direct attack by A or B at electrophilic
transition metal complexes may also be possible.
Received: July 2, 2012
Published online: && &&, &&&&
[8] a) P. Knochel, R. D. Singer, Chem. Rev. 1993, 93, 2117; b) E.
Erdik, Organozinc Reagents in Organic Synthesis, CRC, Boca
Raton, 1996; c) P. Knochel, J. J. A. Perea, P. Jones, Tetrahedron
1998, 54, 8275; d) Organozinc Reagents, A Practical Approach
(Eds.: P. Knochel, P. Jones), Oxford University Press, Oxford,
1999; e) P. Knochel, N. Millot, A. L. Rodriquez, C. E. Tucker,
Org. React. 2001, 58, 417.
Keywords: allylation · copper · small ring systems ·
.
synthetic methods · zinc
[9] a) B. H. Lipshutz, S. Sengupta, Org. React. 1992, 41, 135;
b) Modern Organocopper Chemistry (Ed.: N. Krause), Wiley-
VCH, Weinheim, 2002.
[10] Cf; a) P. Knochel, T.-S. Chou, H. G. Chen, M. C. P. Yeh, M. J.
Rozema, J. Org. Chem. 1989, 54, 5202; b) A. Yanagisawa, Y.
[1] a) E. Nakamura, H. Oshino, I. Kuwajima, J. Am. Chem. Soc.
1986, 108, 3745; b) E. Nakamura, S. Aoki, K. Sekiya, H. Oshino,
I. Kuwajima, J. Am. Chem. Soc. 1987, 109, 8056; c) I. Kuwajima,
E. Nakamura, Top. Curr. Chem. 1990, 155, 1.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Noritake, N. Nomura, H. Yamamoto, Synlett 1991, 251; c) Y.
Yamamoto, M. Tanaka, T. Ibuka, Y. Chounan, J. Org. Chem.
1992, 57, 1024; d) A. Sidduri, M. J. Rozema, P. Knochel, J. Org.
Chem. 1993, 58, 2694; e) N. Harrington-Frost, H. Leuser, M. I.
Calaza, F. F. Kneisel, P. Knochel, Org. Lett. 2003, 5, 2111; f) H.
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g) D. Soorukram, P. Knochel, Angew. Chem. 2006, 118, 3768;
Angew. Chem. Int. Ed. 2006, 45, 3686.
[12] Zinc carbenoid-promoted ring opening of cyclopropanols gave
the regioselective preparation of a-methyl substituted ketones:
P. P. Das, B. B. Parida, J. K. Cha, ARKIVOC 2012, Part (ii), 74.
[13] Enantiopure cyclopropanols were prepared according to pub-
lished methods: a) H. G. Lee, I. L. Lysenko, J. K. Cha, ARKI-
VOC 2008, 9, 133; b) L. G. Quan, S.-H. Kim, J. C. Lee, J. K. Cha,
Angew. Chem. 2002, 114, 2264; Angew. Chem. Int. Ed. 2002, 41,
2160.
[14] Cf. For previous alkylation of cyclohexenyl derivatives with
dialkylcuprates, see: a) H. L. Goering, V. D. Singleton, Jr., J.
Org. Chem. 1983, 48, 1531; b) A. Kreft, Tetrahedron Lett. 1977,
18, 1035.
[11] Use of diethylzinc was prerequisite for allylation. No reaction
was observed in the absence of diethylzinc. Ethylzinc iodide and
zinc carbenoids were ineffective.
[15] Cf. P. Wipf, Y. Uto, S. Yoshimura, Chem. Eur. J. 2002, 8, 1670.
4
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Communications
Synthetic Methods
P. P. Das, K. Belmore,
J. K. Cha*
&&&& — &&&&
Reining in reactivity: Stereoselective SN2’
alkylation of cyclopropanols has been
devised under the control of mixed zinc/
copper reagents. This method provides
convenient access to enantiopure keto
SN2’ Alkylation of Cyclopropanols via
Homoenolates
homoenolates which react with electro-
+
ꢀ
philes (El ) to form C C bonds. M=
metal.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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